Thienyl-containing fatty acid glycosyl phosphatidylinosital analogues used for inhibiting parasitic activity

ABSTRACT

A method of inhibiting parasitic activity is disclosed in which the biosynthesis, structure and/or function of the glycosyl phosphatidylinositol (GPI) anchor of said parasite may be affected by incorporating into said GPI anchor selected analogs of myristic acid containing various heteroatoms, substituents and unsaturated bonds, including ester-containing analogs, ketocarbonyl-containing analogs, sulfur-containing analogs, double bond- and triple bond-containing analogs, aromatic moiety-containing analogs, nitrated analogs and halogenated analogs.

This invention was made in part with government support under grantnumbers A121334, A127179, and A130188, awarded by the NationalInstitutes of Health. The government has certain rights to the invention

This is a division of application Ser. No. 08/617,246, filed Mar. 18,1996, now U.S. Pat. No. 5,760,259 which is a division of applicationSer. No. 08/523,301, filed Sep. 5, 1995, now U.S. Pat. No. 5,747,537.

BACKGROUND OF THE INVENTION

This invention relates to a method of inhibiting parasitic activity byinhibiting the biosynthesis of the glycosyl phosphatidylinositol (GPI)anchor of the parasite. More particularly, the invention relates to theinhibition of parasitic activity by contacting said parasite withselected analogs of myristic acid containing various heteroatoms,substituents and unsaturated bonds.

Glycosyl phosphatidylinositols (GPIs) anchors diverse proteins to theplasma membranes of organisms ranging from the yeasts to mammals. See,e.g., the review article by Low, Biochem. J. 244, 1-13 (1987). One ofthe most completely characterized GPI anchors is that of the variantsurface glycoprotein (VSG) of the parasitic protozoan Trypanosomabrucei. See, e.g., the research article by Ferguson et al. Science 239,753-759 (1988), for the complete primary structure of the GPI anchors ofVSG variant 117, and the review of GPI biosynthesis in T. brucei byEnglund, Ann. Rev. Biochem. 62, 121-138 (1993). This parasite, in commonwith other African trypanosomes, evades the mammalian immune system byantigenic variation in which individual genes encoding immunologicallydistinct VSGs form a dense surface coat. The VSG coat acts as amacromolecular diffusion barrier which protects the parasite from lytichost-serum components.

Trypanosoma brucei is a protozoan bloodstream parasite responsible forAfrican sleeping sickness which has a devastating effect on human healthand on livestock production. Consequently, methods of inhibiting theactivity of this and related protozoan parasites would have significantimportance to medical science and for the development of therapeuticintervention to parasitic diseases.

Recently, in U.S. Pat. No. 5,151,445, certain myristic acid analogs havebeen disclosed as useful for inhibiting the growth and viability ofbloodstream trypanosome parasites having a GPI membrane anchor. Theseanalogs are oxy-substituted fatty acid analogs of C₁₃ and C₁₄ fattyacids or alkyl esters thereof in which a methylene group normally incarbon position from 4 to 13 of said fatty acid is replaced with oxygen.See also Doering et al., Science 252, 1851-1854 (1991).

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, a method is provided forinhibiting parasitic activity of a bloodstream trypanosome parasitewhich comprises contacting said parasite with a compound selected from agroup of myristic acid analogs containing various heteroatoms,substituents and unsaturated bonds. For purposes of convenience, these53 selected analogs are divided into the following sub-groups with theirchemical formulas being shown.

THIATETRADECANOIC ACIDS

CH₃ --S--(CH₂)₁₁ --COOH

CH₃ --CH₂ --S--(CH₂)₁₀ --COOH

CH₃ --(CH₂)₃ --S--(CH₂)₈ --COOH

CH₃ --(CH₂)₄ --S--(CH₂)₇ --COOH

CH₃ --(CH₂)₅ --S--(CH₂)₆ --COOH

CH₃ --(CH₂)₆ --S--(CH₂)₅ --COOH

CH₃ --(CH₂)₇ --S--(CH₂)₄ --COOH

CH₃ --(CH₂)₈ --S--(CH₂)₃ --COOH

OXYGEN AND SULFUR CONTAINING ANALOGS

CH₃ --CH₂ --S--(CH₂)₂ --O--(CH₂)₇ --COOH

OXOTETRADECANOIC ACIDS

CH₃ --CO--(CH₂)₁₁ --COOH

CH₃ --(CH₂)₂ --CO--(CH₂)₉ --COOH

CH₃ --(CH₂)₃ --CO--(CH₂)₈ --COOH

CH₃ --(CH₂)₄ --CO--(CH₂)₇ --COOH

CH₃ --(CH₂)₆ --CO--(CH₂)₅ --COOH

CH₃ --(CH₂)₈ --CO--(CH₂)₃ --COOH

CH₃ --(CH₂)₉ --CO--(CH₂)₂ --COOH

ESTER-CONTAINING ANALOGS

CH₃ --O--CO--(CH₂)₁₀ --COOH

CH₃ --(CH₂)₂ --O--CO--(CH₂)₈ --COOH

CH₃ --(CH₂)₃ --O--CO--(CH₂)₇ --COOH

CH₃ --(CH₂)₅ --O--CO--(CH₂)₅ --COOH

CH₃ --(CH₂)₆ --O--CO--(CH₂)₄ --COOH

CH₃ --(CH₂)₇ --O--CO--(CH₂)₃ --COOH

CH₃ --(CH₂)₈ --O--CO--(CH₂)₂ --COOH

NITROALKYLCARBOXYLIC ACIDS

O₂ N--(CH₂)₁₂ --COOH

O₂ N--(CH₂)₁₀ --COOH

HALOGENATED ANALOGS

Br--(CH₂)₁₂ --COOH

Br--(CH₂)₁₃ --COOH

TETRADECENOIC ACIDS

CH₃ --CH₂ --CH═CH--(CH₂)₉ --COOH

CH₃ --(CH₂)₅ --CH═CH--(CH₂)₅ --COOH

CH₃ --(CH₂)₆ --CH═CH--(CH₂)₄ --COOH

TETRADECADIENOIC ACIDS

CH₃ --(CH₂)₄ --CH═CH--CH═CH--(CH₂)₄ --COOH

CH₃ --(CH₂)₅ --CH═CH--CH═CH--(CH₂)₃ --COOH

TETRADECYNOIC ACIDS

HC.tbd.C--(CH₂)₁₁ --COOH

CH₃ --(CH₂)₂ --C.tbd.C--(CH₂)₈ --COOH

CH₃ --(CH₂)₃ --C.tbd.C--(CH₂)₇ --COOH

CH₃ --(CH₂)₄ --C.tbd.C--(CH₂)₆ --COOH

CH₃ --(CH₂)₅ --C.tbd.C--(CH₂)₅ --COOH

CH₃ --(CH₂)₆ --C.tbd.C--(CH₂)₄ --COOH

CH₃ --(CH₂)₇ --C.tbd.C--(CH₂)₃ --COOH

CH₃ --(CH₂)₅ --C.tbd.C--(CH₂)₄ --COOH

AROMATIC MOIETY-CONTAINING ANALOGS 11 Carbon Equivalent Length

C₆ H₅ --(CH₂)₇ --COOH

13 Carbon Equivalent Length

C₆ H₅ --(CH₂)₉ --COOH

CH₃ --CH₂ --C₆ H₄ --(CH₂)₇ --COOH

CH₃ --(CH₂)₃ --O--C₆ H₄ --(CH₂)₄ --COOH

14 Carbon Equivalent Length

C₆ H₅ --(CH₂)₁₀ --COOH

CH₃ --(CH₂)₄ --O--C₆ H₄ --(CH₂)₄ --COOH

CH₃ --(CH₂)₃ --O--C₆ H₄ --CH═CH--(CH₂)₃ --COOH

CH₃ (CH₂)₄ --O--C₆ H₄ --CH═CH--(CH₂)₂ --COOH

HETERO-AROMATIC ANALOGS

CH₃ --(CH₂)₆ -furyl-(CH₂)₃ --COOH

CH₃ --(CH₂)₅ -furyl-(CH₂)₄ --COOH

CH₃ --(CH₂)₄ -furyl-(CH₂)₅ --COOH

2-Furyl-(CH₂)₁₀ --COOH

2-Thienyl-(CH₂)₁₀ --COOH

The chemical structures of the fifteen preferred compounds in theforegoing sub-groups are shown in Table 1 below. These compounds arelisted in the approximate order of their toxic effect upon trypanosomesin culture, with the most toxic compounds at the top of the list. Forpurposes of comparison, the structures of five representativeoxy-myristic acid analogs (oxatetradecanoic acids) disclosed in U.S.Pat. No. 5,151,445, are also included in this list. These fiveoxy-myristic acid analogs are as follows:

11-oxatetradecanoic acid, abbrev. 0-11

10-oxatetradecanoic acid, abbrev. 0-10

8-oxatetradecanoic acid, abbrev. 0-8

7-oxatetradecanoic acid, abbrev. 0-7

5-oxatetradecanoic acid, abbrev. 0-5

                                      TABLE 1                                     __________________________________________________________________________    Activity                                                                        order Compound Structure and systematic name                                __________________________________________________________________________     1  CH.sub.3 (CH.sub.2).sub.3 C.tbd.C(CH.sub.2).sub.7 COOH                                              9-tetradecynoic acid                                   2 CH.sub.3 (CH.sub.2).sub.6 --O--(CH.sub.2).sub.5 COOH 7-oxatetradecano                              ic acid                                                3 CH.sub.3 (CH.sub.2).sub.6 --CO--(CH.sub.2).sub.5 COOH 7-oxotetradecan                              oic acid                                               4 CH.sub.3 (CH.sub.2).sub.6 --S--(CH.sub.2).sub.5 COOH 7-thiatetradecan                              oic acid                                               5 CH.sub.3 (CH.sub.2).sub.8 --S--(CH.sub.2).sub.3 COOH 5-thiatetradecan                              oic acid                                               6 CH.sub.3 (CH.sub.2).sub.7 --O--CO--(CH.sub.2).sub.3 COOH mono-n-octyl                               glutarate                                             7 CH.sub.3 (CH.sub.2).sub.5 --CH═CH--CH═CH--(CH.sub.2).sub.3                                 COOH 5,7-tetradecadienoic acid                         8 CH.sub.3 (CH.sub.2).sub.4 C.tbd.C(CH.sub.2).sub.6 COOH 8-tetradecynoi                              c acid                                                 9 CH.sub.3 (CH.sub.2).sub.3 --O--p-C.sub.6 H.sub.4 --(CH.sub.2).sub.4                                COOH 5-(p-butoxyphenyl)pentanoic acid                 10 CH.sub.3 (CH.sub.2).sub.5 -2,5-C.sub.4 H.sub.2 O--(CH.sub.2).sub.4                                 COOH 5-[2-(5-n-hexylfuryl)]pentanoic acid                                      11 O.sub.2 N--(CH.sub.2).sub.12 COOH 13-nitrotr                              idecanoic acid                                        12 CH.sub.3 (CH.sub.2).sub.4 --O--p-C.sub.6 H.sub.4 --(CH.sub.2).sub.4                                COOH 5-(p-pentoxyphenyl)pentanoic acid                13 CH.sub.3 (CH.sub.2).sub.2 --O--(CH.sub.2).sub.9 COOH 11-oxatetradecan                              oic acid                                              14 CH.sub.3 (CH.sub.2).sub.3 --O--(CH.sub.2).sub.8 COOH 10-oxatetradecan                              oic acid                                              15 CH.sub.3 (CH.sub.2).sub.8 --O--(CH.sub.2).sub.3 COOH 5-oxatetradecano                              ic acid                                               16 CH.sub.3 --S--(CH.sub.2).sub.11 COOH 13-thiatetradecanoic acid                                      17 CH.sub.3 (CH.sub.2).sub.5 --O--(CH.sub.2).su                              b.6 COOH 8-oxatetradecanoic acid                      18 CH.sub.3 (CH.sub.2).sub.8 --O--CO--(CH.sub.2).sub.2 COOH mono-n-nonyl                               succinate                                            19 CH.sub.3 (CH.sub.2).sub.6 --CO--(CH.sub.2).sub.3 COOH 5-oxotetradecan                              oic acid                                              20 CH.sub.3 (CH.sub.2).sub.4 --S--(CH.sub.2).sub.7 COOH 9-thiatetradecan                              oic acid                                            __________________________________________________________________________

DETAILED DESCRIPTION OF THE INVENTION

White the specification concludes with claims particularly pointing outand distinctly claiming the subject matter regarded as forming thepresent invention, it is believed that the invention will be betterunderstood from the following detailed description taken in conjunctionwith the accompanying drawings in which briefly:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar graph which shows: Assay of analog toxicity. Thetoxicity of 16 compounds, identified only by code number was assessedrelative to 11-oxatetradecanoic acid (0-11) and ethanol (E) controls.Each bar shows the mean and standard deviation of quadruplicate assays.All compounds were tested at 10 μM. The 0.1% ethanol in control E,corresponding to the final concentration of solvent present in otherassays, had no effect on growth. Brackets on the right of the graphindicate the efficacy group designations for this test. As described inMethods herein below, 11-oxatetradecanoic acid and ethanol controls aredefined as the middle value of groups 1 and 3, respectively. Compoundcodes corresponded to the following structures: 21, CH₃ --(CH₂)₃--CO--(CH₂)₈ --COOH; 22, CH₃ --(CH₂)₇ --NH--CO--(CH₂)₃ --COOH; 23, CH₃--(CH₂)₅ --COOH; 24, ethanol; 25, CH₃ --(CH₂)₄ --CO--(CH₂)₇ --COOH; 26,CH₃ --(CH₂)₁₀ --CO--CH₂ --COOH; 27, CH₃ (CH₂)₂ --O--(CH₂)₉ COOH(11-oxatetradecanoic acid); 28, CH₃ --(CH₂)₈ --CO--(CH₂)₃ --COOH; 29,CH₃ --(CH₂)₆ --NH--CO--(CH₂)₄ --COOH; 30, CH₃ --CH₂ --CO--(CH₂)₁₀--COOH; 31, CH₃ --(CH₂)₅ --CO--(CH₂)₆ --COOH; 32, CH₃ --(CH₂)₉--CO--(CH₂)₂ --COOH; 33, CH₃ --(CH₂)₂ --CO--(CH₂)₉ --COOH; 34, CH₃--(CH₂)₈ --NH--CO--(CH₂)₂ --COOH; 35, CH₃ --CO--(CH₂)₁₁ --COOH; 36, CH₃--(CH₂)₇ --CO--(CH₂)₄ --COOH.

FIGS. 2A and 2B show the chemical structures of the 20 myristate analogsmost toxic to trypanosomes arranged into structural groups.

Most of the myristic acid analogs used in the method of the presentinvention are well-known compounds which have been previously describedas useful antiviral agents. See, e.g., Bryant et al., Proc. Natl. Acad.Sci. USA 86, 8655-8659 (1989), and Bryant et al., IBID. 88, 2055-2059(1991). In their activity as antiparasitic agents in the presentinvention, these myristic analogs function in a different manner than asantiviral agents. In their antiviral activity, these compounds serve assubstrates of myristoyl CoA:protein N-myristoyltransferase, an enzymewhich transfers myristate from myristoyl CoA to the amino terminalglycine residue of eukaryotic cellular and viral protein. In theirantiparasitic activity, these compounds are incorporated into the GPIanchor of the parasite. However, the antiparasitic activity may also bemediated, in part, by alteration of N-myristoylated proteins, or by somechange in membrane structure caused by incorporation of the myristicacid analog into phospholipids.

The syntheses of the myristic acid analogs used in the method of thepresent invention also are well-known. Thus, the synthesis ofsulfur-containing myristic acid analogs is described, e.g., byHeuckeroth et al., J. Biol. Chem. 263, 2127-2133 (1988), Heuckeroth etal., Proc. Natl. Acad. Sci. USA 85, 8795-8799 (1988), and in U.S. Pat.Nos. 5,073,571 and 5,082,967. Double bond- and triple bond-containingmyristic acid analogs are also described in said patents, in Heuckerothet al., Proc Natl. Acad. Sci. USA 85, 8795-8799 (1988), and in Rudnicket al., Proc. Natl. Acad. Sci. USA 89, 10507-10511 (1992). Synthesis ofazido-substituted myristic acid analogs is described in EP 480,901. Thepreparation of many of these and other such myristic acid analogscontaining oxygen, sulfur, double bond, triple bond and aromaticresidues is described in Kishore et al., J. Biol. Chem. 266, 8835-8855(1991). Synthesis of myristic acid analogs containing carbonyl groups,nitrogen heteroatoms and nitrogen heterocycles is described in Devadaset al., J. Biol. Chem. 267, 7224-7239 (1992). The synthesis of stillother such triple bond- and aromatic moiety-containing analogs ofmyristic acid is described by Gokel et al., Israel J. Chem. 32, 127-133(1992). Examples 1-43, below, illustrate the synthesis of 40 additionaltest compounds.

In order to illustrate the invention in greater detail, a total of 247different myristic acid analogs (listed in Table 2, below) were testedfor toxicity to trypanosomes in culture in accordance with astate-of-the-art assay. For comparison the testing included fiveoxy-myristic acid analogs (oxatetradecanoic acids) described in U.S.Pat. No. 5,151,445, the disclosure of which is incorporated herein byreference. Based on the test results, these 247 compounds were dividedinto three efficacy groups in which groups 2 and 3 consisted of the 60active compounds whereas the 177 compounds of group 1 were inactive. Ofthe active compounds, the 20 compounds in group 3 were the most active.Although specific examples of the invention are thus illustrated herein,it will be understood that the invention is not limited to thesespecific examples or the details described therein. References to showthe state-of-the-art are indicated in parentheses and appended at theend.

EXAMPLES Materials and Methods

Materials--Fetal calf serum, hypoxanthine, MEM "alpha" medium (320-2561AJ), penicillin, pyruvate, streptomycin and thymidine were obtained fromGibco/BRL. Other reagents, where not specified, were from Sigma ChemicalCo.

Synthesis of Fatty Acid Analogs

The methods used for synthesizing 203 of the 247 fatty acids shown inTable 1 are described in published reports (Rapaport and Newman, 1947;Kishore et al., 1991; Devadas et al., 1992; Gokel et al., 1992; Rudnicket al., 1992; footnote 3). The methods used to synthesize 40 additionalfatty acids included in the panel are described below.

Chemical Analysis

Melting points were measured on a Laboratory Devices MEL-TEMP apparatusin open capillaries and are uncorrected. ¹ H-NMR spectra were recordedon a Hitachi Perkin-Elmer R-600 high resolution NMR spectrometer and ona Varian VXR 400 superconducting NMR. Spectra were obtained in CDCl₃ andare reported in ppm (δ) downfield from internal Me₄ Si. IR spectra wererecorded on a Perkin-Elmer Model 298 or 599 infrared spectrophotometer.TLC analyses were performed on silica gel 60F-254 plates (thickness=0.20mm; Merck). Column chromatography was carried out with Merck Kieselgel60 (70-230 mesh). Combustion analyses were conducted by AtlanticMicrolab Inc., Atlanta, Ga. High resolution mass spectrometry wasconducted at the Southern California Mass Spectrometer Facility,Department of Chemistry, University of California, Riverside. The CI/NH₃experiments did not typically show MH+ ions so high resolution massspectrometry was done on MNH₄ ⁺ ions.

General Procedure for Wittig Reaction

Phosphonium bromide was treated with potassium t-butoxide intetrahydrofuran (THF) under nitrogen with stirring for 30 min. Thesolution was cooled with ice. Aldehyde in THF was added dropwise, andthe mixture was stirred for 12 h. The mixture was poured into water (150mL), washed with Et₂ O (50 mL), acidified (pH=1, 2N HCl) and extracted(hexanes, 4×50 mL), dried over MgSO₄, and the solvent was removed invacuo. Chromatography (silica gel, 1:1 hexanes-ethyl acetate) andcrystallization or Kugelrohr distillation yielded the product.

General Procedure for Hydrolysis Reaction

A nitrile or ester containing compound, sodium hydroxide H₂ O (20 mL),and EtOH (20 mL) were mixed and refluxed for 16 h. The mixture wascooled to room temperature, acidified (pH=1, 2N HCl), and extracted withethyl acetate (4×50 mL). The organic solution was washed with water(2×50 mL), dried over MgSO₄ and evaporated. The residue was crystallizedor distilled to afford the product.

General Procedure for Hydrogenation Reaction

An unsaturated compound, 5% Pd/C or Pd/BaSO₄ and anhydrous EtOH (50 mL)were shaken under 15 psi H₂ for 1.0-4.0 h. The catalyst was filtered andwashed with EtOH (2×15 mL). The solvent was evaporated in vacuo. Theresidue was crystallized or Kugelrohr distilled to afford the product.

TETRADECANDIENOIC ACIDS Example 1

8,10-Tetradecandienoic acid

This compound was synthesized from 7-carboxyheptyltriphenylphosphoniumbromide (9.71 g, 20 mmol) and 2-trans-hexenal (1.96 g, 20 mmol) in 10%hexamethylphosphoric triamide (HMPA)-THF (100 mL) by a Wittig reaction.Kugelrohr distillation yielded the product (1.97 g, 44%) as a yellow oil(bp 123-126° C./0.01 torr). IR: 3450-2500, 1720 cm⁻¹ ; ¹ H-NMR; 0.95 (t,3H), 1.35 (m, 8H), 1.62 m, 2H), 2.05 (m, 4H), 2.32 (t, 2H), 5.23 (m,1H), 5.60 (m, 1H), 5.90 (m, 1H), 6.05 (m, 1H), 10.50 (bs, 1H). Anal.Calcd. for C₁₄ H₂₄ O₂ : C, 74.95, H, 10.78%; Found: C, 75.01, H, 10.80%.

Example 2

6,8-Tetradecanedienoic acid

This compound was synthesized from 5-carboxypentyltriphenylphosphoniumbromide (9.50 g, 20 mmol) and 2-trans-octenal (2.52 g, 20 mmol) in10%HMPA-THF (100 mL) by Wittig reaction. Kugelrohr distillation yieldedthe product (1.91 g, 43%) as a pale yellow oil (bp 122-125° C./0.01torr). IR: 3500-2500, 1730 cm⁻¹ ; ¹ H-NMR: 0.95 (t, 3H), 1.40 (m, 10H),2.30 (m, 6H), 6.00 (m, 4H), 11.30 (bs, 1H). Anal. Calcd. for C₁₄ H₂₄ O₂: C, 74.95, H, 10.78%; Found: C, 75.04, H, 10.80%.

Example 3

5,7-Tetracanedienoic acid

This compound was synthesized from 4-carboxybutyltriphenylphosphoniumbromide (8.87 g, 20 mmol) and 2-trans-nonenal (2.80 g, 20 mmol) in10%HMPA-THF (100 mL) by a Wittig reaction. Kugelrohr distillationafforded the product (1.96 g, 44%) as a pale yellow oil (bp 116-119°C./0.01 torr). IR: 3500-2500, 1730 cm⁻¹ ; ¹ H-NMR: 0.90 (t, 3H), 1.35(m, 10H), 2.30 (m, 6H), 5.90 (m, 4H), 10.05 (bs, 1H). Anal. Calcd. forC₁₄ H₂₄ O₂ : C, 74.95, H, 10.78%; Found: C, 74.87, H, 10.79%.

AROMATIC ANALOGS Example 4

8-Phenoxyoctanoic acid

Phenol (1.88 g, 20 mmol) was mixed with NaOH (0.80 g, 20 mmol) in EtOH(50 mL). 8-Bromooctanoic acid (2.23 g, 10 mmol) was then added to themixture and refluxed for 12 h. After cooling to room temperature, water(100 mL) was added and the mixture was acidified with 2N HCl (pH=2). Thesolid was filtered and washed with water (2×50 mL), and recrystallizedfrom hexane-ethyl acetate (5:1) to give the product as white brick-likecrystals (1.79 g, 76%), mp 67-68° C.; ¹ H-NMR: 1.42 (m, 6H), 1.65 (m,2H), 1.80 (m, 2H), 2.37 (t, 2H), 3.97 (t, 2H), 6.93 (m, 3H), 7.30 (t,2H), 10.05 (bs, 1H). Anal. Calcd. for C₁₄ H₂₀ O₃ : C, 71.16, H, 8.53%;Found: C, 71.09, H, 8.54%.

Example 5

8(p-Methoxyphenyl)-7-octennitrile

This compound was synthesized from 6-cyanohexyltriphenylphosphoniumbromide (9.05 g, 20 mmol) and p-anisaldehyde (2.72 g, 20 mmol) in THF(100 mL) by a Wittig reaction. Kugelrohr distillation afforded theproducts (3.26 g, 71%) as a colorless liquid (bp: 143-146° C./0.05torr). IR: 2285 cm⁻¹ ; ¹ H-NMR: 1.50 (m, 6H), 2.30 (m, 4H), 3.80 (s,3H), 5.50 (m, 1H), 6.30 (d, 1H), 7.05 (q, 4H).

Example 6

8-(p-Methoxyphenyl)-7-octenoic acid

This compound was synthesized from 8-(p-methoxyphenyl)-7-octennitrile(3.34 g, 15 mmol) by a hydrolysis reaction. Crystallization(hexanes-ethyl acetate) yielded the product (3.29 g, 88%) as whitecrystals (mp 42-43° C.). IR: 3400-2500, 1730 cm⁻¹ ; ¹ H-NMR: 1.50 (m,6H), 2.35 (m, 4H), 3.82 (s, 3H), 5.55 (m, 1H), 6.35 (d, 1H), 7.05 (q,4H), 11.20 (bs, 1H). Anal. Calcd. for C₁₅ H₂₀ O₂ : C, 72.55, H, 8,12%Found: C, 72.41, H, 8.07%, Z:E=67:33.

Example 7

8-(p-Methoxyphenyl)octanoic acid

This compound was synthesized from 8-(p-methoxyphenyl)-7-octenoic acid(1.24 g, 5 mmol) and Pd/BaSO₄ (125 mg) by hydrogenation. Crystallization(petroleum ether) afforded the product (1.20 g, 96%) as white crystals(mp 42-43° C.). IR: 3400-2500, 1705 cm⁻¹ ; ¹ H-NMR: 1.40 (m, 10H), 2.40(m, 4H), 3.80 (s, 3H), 6.95 (q, 4H), 10.10 (bs, 1H). Anal. Calcd. forC₁₅ H₂₂ O₂ : C, 71.97, H, 8.86%; Found: C, 72.07, H, 8.88%.

Example 8

7-(p-Ethoxyphenyl)-6-heptenoic acid

This compound was synthesized from 5-carboxypentyltriphenylphosphoniumbromide (9.50 g, 20 mmol) and p-ethoxybenzaldehyde (3.00 g, 20 mmol) inTHF (100 mL) by a Wittig reaction. Crystallization (hexanes-ethylacetate) afforded the product (3.18 g, 64%) as white crystals (mp 62-63°C.), IR: 3450-2500, 1720 cm⁻¹ ; ¹ H-NMR: 1.40 (t, 3H), 1.50 (m, 2H),1.70 (m, 2H), 2.38 (m, 4H), 4.00 (q, 2H), 5.72+6.05 (m, 1H), 6.32 (t,1H), 7.05 (q, 4H), 10.10 (bs, 1H). Anal. Calcd. for C₁₅ H₂₀ O₃ : C,72.55, H, 8.12% Found: C, 72.53, H, 8.15%. Z:E=45:55.

Example 9

7-(p-Ethoxyphenyl)heptanoic acid

This compound was synthesized from 7-(p-ethoxyphenyl)-6-heptenoic acid(1.24 g, 5 mmol) and Pd/C (125 mg) by a hydrogenation reaction.Crystallization (petroleum ether) afforded the product (1.21 g, 97%) aswhite crystals (mp 65-66° C). IR: 3400-2500, 1715 cm⁻¹ ; ¹ H-NMR: 1.32(m, 7H), 1.55 (m, 5H), 2.30 (t, 2H), 2.50 (t, 2H), 3.95 (q, 2H), 6.90(q, 2H), 10.20 (bs, 1H). Anal. Calcd. for C₁₅ H₂₂ O₃ : C, 71.97, H,8.86%; Found: C, 71.91, H, 8.87%.

Example 10

6-(p-Propoxyphenyl)-5-hexenoic acid

This compound was synthesized from 4-carboxybutyltriphenylphosphoniumbromide (8.87 g, 20 mmol) and p-propoxybenzaldehyde (3.28 g, 20 mmol,synthesized from p-hydroxybenzaldehyde and 1-iodopropane) in THF (100mL) by a Wittig reaction. Crystallization (petroleum ether) afforded theproduct (3.75 g, 76%) as white crystals (mp, 49-50° C.). IR: 3400-2500,1725 cm⁻¹ ; ¹ H-NMR: 1.00 (t, 3), 1.75 (m, 4H), 2.35 (m, 4H), 3.90 (t,2H), 5.55 (m, 1H), 6.35 (m, 1H), 7.00 (q, 4H), 11.30 (bs, 1H). Anal.Calcd. for C₁₅ H₂₀ O₃ : C, 72.55, H, 8.12%; Found: C, 72.45, H, 8.13%.Z:E=35:65.

Example 11

6-(p-Propoxyphenyl)hexanoic acid

This compound as synthesized from 6-(p-propoxyphenyl)-5-hexanoic acid(1.49 g, 6 mmol) and Pd/BaSO₄ (150 mg) by a hydrogenation reaction.Crystallization (petroleum ether) yielded the product (1.38 g, 92%) aswhite crystals (mp 42-43° C.), IR: 3400-2500, 1715 cm⁻¹ ; ¹ H-NMR: 1.00(t, 3H), 1.55 (m, 8H), 2.40 (m, 4H), 3.90 (t, 2H), 6.95 (q, 4H), 7.90(bs, 1H). Anal. Calcd. for C₁₅ H₂₂ O₃ : C, 71.97, H, 8.86%; Found: C,72.04, H, 8.88%.

GENERAL PROCEDURE FOR THE PREPARATION OF ARYL-TERMINAL ACIDS Example 12

9-Phenoxynonanoic acid

A. 7-Phenoxyheptyl bromide

Phenol (3.10 g, 33 mmol), 1,7-dibromoheptane (7.74 g, 30 mmol) and NaOH(1.34 g, 33 mmol) were refluxed in EtOH (40 mL) for 30 h. After coolingto room temperature, water (150 mL) was added and the mixture wasextracted with ethyl acetate (4×50 mL). The organic phase was washedwith water (50 mL) and brine (50 mL), and the mixture was dried over Na₂SO₄. After evaporation of solvent, the residue was purified by Kugelrohrdistillation to give 7-phenoxyheptyl bromide (2.46 g, 30%), bp 126-130°C./0.10 torr, ¹ H-NMR: 1.2-1.9 (m, 10H), 3.36 (t, 2H), 3.91 (t, 2H),6.7-7.2 (m, 5H).

B. Ethyl 2-ethoxycarbonyl-9-phenoxynonanoate

Sodium (0.22 g, 9.6 mmol) was dissolved in EtOH (20 mL). Diethylmalonate (1.53 g, 9.6 mmol) in EtOH (5 mL) and 7-phenoxyheptyl bromide(2.36 g, 8.7 mmol) in EtOH (5 mL) were subsequently added at roomtemperature. The reaction mixture was refluxed for 8 h. Afterevaporation of the solvent, the residue was taken up in ethyl acetate(150 ml). The organic phase was washed with water (2×50 mL), and brine(50 mL), and dried over Na₂ SO₄. The crude product was purified byKugelrohr distillation to give ethyl 2-ethoxycarbonyl-9-phenoxynonanoate(1.92 g, 63%), bp 150-154° C./0.1 torr, ¹ H-NMR: 1.24 (t, 6H), 1.1-1.8(m, 12H), 3.30 (t, 1H), 3.91 (t, 2H), 4.18 (q, 4H), 6.7-7.2 (m, 5H).

C. 9-Phenoxynonanoic acid

A solution of ethyl 2-ethoxycarbonyl-9-phenoxynonanoate (1.84 g, 5.3mmol) in 20% NaOH (20 mL) was refluxed for 10 h. The solution wasacidified with HCl(pH=2) and extracted with ethyl acetate (3×50 mL). Theorganic phase was washed with water (2×30 mL), and brine (30 mL), anddried over Na₂ SO₄. After removal of the solvent in vacuo, the residuewas heated on an oil bath at 180-200° C. for 10 min. The crude productwas distilled (Kugelrohr) followed by crystallization (hexane) to givethe product (1.14 g, 85%), mp 66.5-67.5° C. (lit.³ 68-69° C.). IR:3450-2500, 1720 cm⁻¹ ; ¹ H-NMR: 1.26-1.39 (m, 8H), 1.61 (q, 2H), 1.75(q, 2H), 2.34 (t, 2H), 3.93 (t, 2H), 6.83-6.96 (m, 3H), 7.28 (t, 2H),10.8 (bs, 1H).

Example 13

9-Phenylthionanoic acid

A. 7-Phenylthioheptyl bromide was prepared from thiphenol (4.40 g, 40mmol) and 1,7-dibromoheptane (10.32 g, 40 mmol) as described above for7-phenoxyheptyl bromide. Yield: 46% bp; 132-136° C./0.05 torr; ¹ H-NMR:1.30-1.85 (m, 10H), 2.90 (t, 2H), 3.35 (t, 2H), 7.25 (s, 5H).

B. Ethyl 2-ethoxycarbonyl-9-phenylthiononanoate was prepared from7-phenylthioheptyl bromide (4.31 g, 15 mmol) and diethyl malonate (3.20g, 20 mmol) according to the procedure given above. Yield: 68%, bp:174-178° C./0.05 torr; ¹ H-NMR: 1.15-1.90 (m, 18H), 2.90 (t, 2), 3.30(t, 1H), 4.20 (q, 4H), 7.25 (s, 5H).

C. 9-Phenylthiononanoic acid was obtained from ethyl2-ethoxycarbonyl-9-phenylthiononanoate (3.66 g, 10 mmol) by basichydrolysis as described above. Yield: 82%, mp 67-68° C.; IR: 3450-2550,1695 cm⁻¹ ; ¹ H-NMR: 1.20-1.80 (m, 12H), 2.35 (t, 2H), 2.85 (t, 2H),7.20 (s, 5H), 10.50 (bs, 1H). Anal. Calcd. for C₁₅ H₂₂ O₂ S: C, 67.63;H, 8.32; S, 12.03%. Found: C, 67.54; H, 8.31; S, 12.09%.

Example 14

8-Benzyloxyoctanoic acid

A. 6-Benzyloxyhexyl bromide was prepared from benzyl alcohol (4.75 g, 44mmol) and 1,6-dibromohexane (9.76 g, 40 mmol) using the generalprocedure given above. Yield: 36%, bp 100-105° C./torr: ¹ H-NMR: 1.2-1.9(m, 8H), 3.37 (t, 4H), 4.46 (s, 2H), 7.28 (m, 5H).

B. Ethyl 2-ethoxycarbonyl-8-benzyloxyoctanoate was prepared from6-benzyloxyhexyl bromide (3.52 g, 13 mmol) and diethyl malonate (2.29 g,14 mmol) according to the general procedure given above. Yield 60%, bp152-158° C./0.15 torr. ¹ H-NMR: 1.24 (t, 6H), 1.2-1.9 (m, 10H), 3.43 (t,2H), 4.18 (q, 4H), 4.45 (s, 2H), 7.27 (m, 5H).

C. 8-Benzyloxyoctanoic acid was prepared from ethyl2-ethoxycarbonyl-8-benzyloxyoctanoate (2.6 g, 7.4 mmol) by basichydrolysis as described above. Yield: 83%, bp 158-162° C./0.15 torr; IR:3450-2550, 1710 cm⁻¹ ; ¹ H-NMR: 1.24-1.43 (m, 6H), 1.54-1.69 (m, 4H),2.31 (t, 2H), 3.46 (t, 2H), 4.51 (s, 2H), 7.23-7.38 (m, 5H), 9.55 (bs,1H). Anal. Calcd. for C₁₅ H₂₂ O₃ : C, 71.97; H, 8.86%. Found: C, 71.83;H, 8.90%.

Example 15

8-Benzylthiooctanoic acid

A. Ethyl 8-benzylthiooctanoate. NaH (0.63 g, 16 mmol) was washed withhexane and then suspended in dry THF (60 mL). Benzylmercaptan (1.86 g,15 mmol) in THF (20 mL) was added and the mixture stirred for 30 min atroom temperature. Ethyl 8-iodooctanoate (4.47 g, 15 mmol) in THF (20 mL)was added and the mixture was refluxed for 12 h. After evaporation ofthe solvent, the residue was dissolved in ethyl acetate (150 mL). Theorganic phase was washed with water (2×50 mL), and brine (50 mL) anddried over Na₂ SO₄. The crude product was purified by columnchromatography on silica gel with ethyl acetate:hexane (1:5) andsubsequent Kugelrohr distillation to give ethyl 8-benzylthiooctanoate(3.7 g, 84%), bp 134-138° C./0.15 torr. ¹ H-NMR: 1.21 (t, 3H), 1.2-1.8(m, 10H), 2.27 (t, 4H), 3.68 (s, 2H), 4.09 (q, 2H), 7.24 (m, 5H).

B. 8-Benzylthiooctanoic acid. A solution of ethyl 8-benzylthiooctanoate(2.94 g, 10 mmol) and 1M NaOH (60 mL, 60 mmol) in MeOH (30 mL) washeated at 70° C. for 6 h. The reaction mixture was acidified with HCl(pH=1) and extracted with ethyl acetate (150 mL). The organic phase waswashed with water (2×50 mL), and brine (50 mL) and dried over Na₂ SO₄.The crude product was purified by crystallization from hexane to affordthe product (2.45 g, 92%), mp 37-37.5° C.; IR: 3400-2500, 1700 cm⁻¹ ; ¹H-NMR: 1.18-1.43 (m, 6H), 1.52 (q, 2H), 1.61 (q, 2H), 2.33 (t, 2H), 2.39(t, 2H), 3.69 (s, 2H), 7.12-7.38 (m, 5H), 9.45 (bs, 1H). Anal. Calcd.for C₁₅ H₂₂ SO₂ : C, 67.63, H, 8.32%; Found: C, 67.74, H, 8.35%.

Example 16

8-(p-Propylphenyl)-7-octenenitrile. This compound was synthesized from6-cyanohexyltriphenylphosphonium bromide (9.05 g, 20 mmol) andp-propylbenzaldehyde (2.96 g, 20 mmol) in THF (100 mL) by a Wittigreaction. Kugelrohr distillation afforded the product (3.25 g, 67%) as acolorless liquid (bp 144-148° C./0.05 torr). IR 2290 cm⁻¹ ; ¹ H-NMR:0.95 (t, 3H), 1.55 (m, 8H), 2.40 (m, 6H), 5.60 (m, 1H), 6.40 (d, 1H),7.10 (s, 4H).

Example 17 8-(p-Propylphenyl)-7-octenoic acid

This compound was synthesized from 8-(p-propylphenyl)-7-octenenitrile(2.41 g, 10 mmol) by a hydrolysis reaction. Kugelrohr distillationafforded the product (2.36 g, 90%) as a colorless oil (bp 148-152°C./0.05 torr). IR: 3400-2500, 1720 cm⁻¹ ; ¹ H-NMR; 0.95 (t, 3H), 1.45(m, 8H), 2.45 (m, 6H), 5.65 (m, 1H), 6.40 (d, 1H), 7.15 (s, 4H), 11.30(bs, 1H). Anal. Calcd. for C₁₇ H₂₄ O₂ : C, 78.42, H, 9.29%; Found: C,78.43, H, 9.30%. Z:E=88:12.

Example 18 8-(p-Propylphenyl)octanoic acid

This compound was synthesized from 8-(p-propylphenyl)-7-octenoic acid(1.30 g, 5 mmol) and Pd/BaSO₄ (130 mg) by a hydrogenation reaction.Crystallization (petroleum ether) afforded the product (1.25 g, 95%) aswhite crystals (mp 42-43° C.). IR: 3400-2500, 1705 cm⁻¹ ; ¹ H-NMR: 0.95(t, 3H), 1.45 (m, 12H), 2.50 (m, 6H), 7.05 (s, 4H), 11.40 (bs, 1H).Anal. Calcd. for C₁₇ H₂₆ O₂ : C, 77.82, H, 9.99%; Found: C, 77.75, H,10.04%.

Example 19 7-(p-Butylphenyl)-6-heptenoic acid

This compound was synthesized from 5-carboxypentyltriphenylphosphoniumbromide (9.50 g, 20 mmol) and p-butylbenzaldehyde (3.24 g, 20 mmol) inTHF (100 mL) by a Wittig reaction. Kugelrohr distillation yielded theproduct (2.67 g, 51%) as a colorless oil (bp 154-157° C./0.05 torr). IR:3400-2500, 1720 cm⁻¹, ¹ H-NMR:0.92 (t, 3H), 1.50 (m, 8H), 2.30 (m, 4H),2.58 (m, 2H), 5.58+6.15 (m, 1H), 6.38 (t, 1H), 7.18 (m, 4H), 10.30 (bs,1H). Anal. Calcd. for C₁₇ H₂₄ O₂ : C, 78.42, H, 9.29%: Found: C, 78.38,H, 9.29%. Z:E=62:38.

Example 20 7-(p-Butylphenyl)heptanoic acid

This compound was synthesized from 7-(p-butylphenyl)-6-heptenoic acid(1.30 g, 5 mmol) by a hydrogenation reaction using Pd/C (130 mg).Crystallization (petroleum ether) afforded the product (1.19 g, 97%) aswhite crystals (mp 32-33° C.). IR: 3400-2500, 1718 cm⁻¹ ; ¹ H-NMR:0.92(t, 3H), 1.35 (m, 6H), 1.60 (m, 6H), 2.32 (t, 2H), 2.55 (m, 4H), 7.02(s, 4H), 9.70 (bs, 1H). Anal. Calcd. for C₁₇ H₂₆ O₂ : C, 77.82, H,9.99%; Found: C, 77.73, H, 10.01%.

Example 21 6-(p-Pentylphenyl)-5-hexenoic acid

This compound was synthesized from p-pentylbenzaldehyde (3.52 g, 20mmol, prepared from p-pentylbenzoyl chloride and lithiumtri(t-butoxy)aluminum hydride) and 4-carboxybutyltriphenylphosphoniumbromide (8.86 g, 20 mmol) in THF (100 mL) by a Wittig reaction.Kugelrohr distillation (bp 147-151° C./0.05 torr) afforded the product(2.49 g, 48%). IR: 3400-2500, 1725 cm⁻¹ ; ¹ H-NMR: 0.90 (t, 3H), 1.28(m, 6H), 1.82 (m, 2H), 1.37 (m, 4H), 2.57 (t, 2H), 5.55+6.10 (m, 1H),6.38 (m, 1H), 7.10 (m, 4H), 10.50 (bs, 1H). Anal. Calcd. for C₁₇ H₂₄ O₂: C, 78.42, H, 9.29%; Found: C, 78.22, H, 9.27%. Z:E=35:65.

Example 22 6-(p-Pentylphenyl)hexanoic acid

This compound was synthesized from 6-(p-pentylphenyl)-5-hexenoic acid(1.30 g, 5 mmol) by hydrogenation reaction using Pd/C (130 mg).Crystallization (petroleum ether) afforded the product (1.13 g, 87%) aswhite crystals (mp 29-30° C.), IR: 3400-2500, 1730 cm⁻¹ ; ¹ H-NMR: 0.89(t, 3H), 1.32 (m, 6H), 1.60 (m, 6H), 2.35 (t, 2H), 2.58 (m, 4H), 7.07(s, 1H), 10.30 (bs, 1H). Anal. Calcd. for C₁₇ H₂₆ O₂ : C, 77.82, H,9.99%; Found: C, 77.56, H, 9.90%.

Example 23 7-(p-Propoxyphenyl)-6-heptenoic acid

This compound was synthesized from p-propoxybenzaldehyde (3.26 g, 20mmol, prepared from 1-bromopropane and 4-hydroxybenzaldehyde) and5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) in THF(100 mL) by a Wittig reaction. Crystallization (petroleum ether)afforded the product (3.15 g, 60%) as white crystals (mp: 52-53° C.).IR: 3450-2500, 1730 cm⁻¹ ; ¹ H-NMR: 1.00 (t, 3H), 1.48 (m, 2H), 1.67 (m,2H), 1.82 (m, 2H), 2.35 (m, 4H), 3.92 (t, 2H), 5.72+6.05 (m, 1H), 6.35(d, 1H), 7.05 (q, 4H), 10.40 (bs, 1H). Anal. Calcd. for C₁₆ H₂₂ O₃ : C,73.25, H, 8.45%. Found: C, 73.15, H, 8.45%. Z:E=30:70.

Example 24 7(p-Propoxyphenyl)heptanoic acid

This compound was synthesized from 7-(p-propoxyphenyl)-6-heptenoic acid(1.31 g, 5 mmol) by hydrogenation reaction using Pd/C(130 mg).Crystallization (petroleum ether) afforded the product (1.23 g, 93%) aswhite crystals (mp: 49-50° C.). IR: 3450-2550, 1725 cm⁻¹ ; ¹ H-NMR: 1.00(t, 3H), 1.37 (m, 4H), 1.60 (m, 4H), 1.79 (m, 2H), 2.36 (t, 2H), 2.53(t, 2H), 3.87 (t, 2H), 6.95 (q, 4H), 9.80 (bs, 1H). Anal. Calcd. for C₁₆H₂₄ O₃ : C, 72.69, H, 9.15%; Found: C, 72.79, H, 9.16%.

Example 25 6-(p-Butoxyphenyl)-5-hexenoic acid

This compound was synthesized from 4-carboxybutyltriphenylphosphoniumbromide (8.86 g, 20 mmol) and p-butoxybenzaldehyde (3.56 g, 20 mmol) inTHF (100 mL) by a Wittig reaction. Crystallization (petroleum ether)afforded the product (3.82 g, 73%) as white crystals (mp: 56-57° C.).IR: 3350-2500, 1700 cm⁻¹ ; ¹ H-NMR: 1.00 (t, 3H), 1.50 (m, 2H), 1.80 (m,4H), 2.40 (m, 4H), 3.90 (t, 2H), 5.50+6.00 (m, 1H), 6.38 (q, 1H), 7.05(q, 4H), 11.00 (bs, 1H). Anal. Calcd. for C₁₆ H₂₂ O₃ : C, 73.25, H,8.45%; Found: C, 73.32, H, 84.6%. Z:E=37:63.

Example 26 6-(p-Butoxyphenyl)hexanoic acid

This compound was synthesized from 6-(p-butoxyphenyl)-5-hexenoic acid(2.62 g, 10 mmol) by a hydrogenation reaction using Pd/C (260 mg).Crystallization (petroleum ether) afforded the product (2.49 g, 94%) aswhite crystals (mp 39-40° C.). IR: 3400=2500, 1705 cm⁻¹ ; ¹ H-NMR: 0.96(t, 3H), 1.35 (m, 2H), 1.50 (m, 2H), 1.62 (m, 4H), 1.75 (m, 2H), 2.35(t, 2H), 2.52 (t, 2H), 3.92 (t, 2H), 6.95 (q, 4H), 10.30 (bs, 1H). Anal.Calcd. for C₁₆ H₂₄ O₃ : C, 72.69, H, 9.15%; Found: C, 72.78, H, 9.18%.

Example 27 Ethyl 8-(4-ethyl)phenoxyoctanoate

NaH (0.25 g, 11 mmol) was washed with hexane and then suspended in dryTHF (50 mL). 4-Ethylphenol (1.22 g, 10 mmol) in THF (20 mL) was addedand stirred for 30 min at room temperature. Ethyl 8-iodooctanoate (2.98g, 10 mmol) in THF (20 mL) was added and the mixture was refluxed for 12h. After evaporation of the solvent, the residue was dissolved in ethylacetate (150 mL), and the organic phase was washed with water (2×50 mL),and brine (50 mL) and dried over Na₂ SO₄. The crude product was purifiedby column chromatography on silica gel (ethyl acetate:hexane=1:5) andsubsequent Kugelrohr distillation to give the product (0.85 g, 24%), bp122-126° C./0.1 torr. IR: 1740 cm⁻¹ ; ¹ H-NMR: 1.19 (t, 3H), 1.25 (t,3H), 1.30-1.80 (m, 10H), 2.28 (t, 2H), 2.57 (q, 2H), 3.90 (t, 2H), 4.12(q, 2H), 6.86 (d, 2H), 7.08 (d, 2H).

Example 28 8-(4-Ethyl)phenoxyoctanoic acid

This compound was synthesized from ethyl 8-(4-ethyl)phenoxyoctanoate(1.76 g, 5 mmol) by a hydrolysis reaction. Crystallization from hexanegive white crystals (1.40 g, 87%), mp 77-78° C.; IR: 3450-2950, 1720cm⁻¹ ; ¹ H-NMR: 1.17 (t, 3H), 1.29-1.49 (m, 6H), 1.63 (q, 2H), 1.74 (q,2H), 2.31 (t, 2H), 2.56 (q, 2H), 3.88 (t, 2H), 6.77 (d, 2H), 7.06 (d,2H), 10.2 (bs, 1H). Anal. Calcd. for C₁₆ H₂₄ O₃ : C, 72.69, H, 9.15%;Found: C, 72.53, H, 9.19%.

Example 29 12-Phenyl-11-dodecenoic acid

This compound was synthesized from 10-carboxydecyltriphenylphosphoniumbromide (10.55 g, 20 mmol) and benzaldehyde (2.12 g, 20 mmol) in THF(100 mL) by a Wittig reaction. Kugelrohr distillation (bp 152-155°C./0.03 torr) and crystallization afforded the product (2.43 g, 44%) aswhite crystals (mp 27-27.5° C.). IR: 3400-2500, 1720, 700 cm⁻¹ ; ¹H-NMR: 1.30 (m, 10H), 1.40 (m, 2H), 1.62 (m, 2H), 2.35 (m, 4H), 5.65 (m,1H), 6.40 (m, 1H), 7.25 (m, 5H), 10.40 (bs, 1H). Anal. Calcd. for C₁₈H₂₆ O₂ : C, 78.79, H, 9.55%; Found: C, 78.66, H, 9.60%. Z:E=93:7.

Example 30 12-Phenyldodecanoic acid

This compound was synthesized from 12-phenyl-10-dodecenoic acid (1.92 g,7 mmol) by a hydrogenation reaction using Pd/C (190 mg). Crystallization(petroleum ether) afforded the product (1.88 g, 97%) as white crystals(mp 47-48° C.). IR: 3400-2500, 1700 cm⁻¹ ; ¹ H-NMR: 1.30 (m, 14H), 1.60(m, 4H), 2.32 (t, 2H), 2.57 (t, 2H), 7.20 (m, 5H), 10.20 (bs, 1H). Anal.Calcd. for C₁₈ H₂₈ O₂ : C, 78.21, H, 10.21%; Found: C, 78.29, H, 10.25%.

HETEROAROMATIC ANALOGS Example 31 9-(2-Furyl)-8-nonenoic acid

This compound was synthesized from 7-carboxyheptyltriphenylphosphoniumbromide (9.71 g, 20 mmol) and 2-furaldehyde (1.92 g, 20 mmol) in THF(100 mL) by a Wittig reaction. Kugelrohr distillation yielded theproduct (2.69 g, 61%) as a pale yellow oil (bp 136-139° C./0.05 torr).IR: 3500-2500, 1730, 710 cm⁻¹ ; ¹ H-NMR: 1.40 (m, 8H), 2.35 (m, 4H),5.55 (m, 1H), 6.30 (m, 3H), 7.35 (s, 1H), 11.40 (bs, 1H). Anal. Calcd.for C₁₃ H₁₈ O₃ : C, 70.25, H, 8.16%; Found: C, 69.98, H, 8.26%.Z:E=79:21.

Example 32 9-(2-Furyl)nonanoic acid

This compound was synthesized from 9-(2-furyl)-8-nonenoic acid (0.89 g,4 mmol) by a hydrogenation reaction using Pd/BaSO₄ (90 mg).Crystallization (petroleum ether) afforded the product (0.84 g, 93%) aswhite crystals (mp 31-32° C.); IR: 3450-2500, 1720 cm⁻¹ ; ¹ H-NMR: 1.30(m, 8H), 1.63 (m, 4H), 2.35 (t, 2H), 2.60 (t, 2H), 5.95 (s, 1H), 6.27(s, 1H), 7.28 (s, 1H), 9.85 (bs, 1H). Anal. Calcd. for C₁₃ H₂₀ O₃ : C,69.61, H, 8.99%; Found: C, 69.42, H, 9.04%.

Example 33 9-(2-(5-Methyl)furyl)-8-nonenoic acid

This compound was synthesized from 5-methylfurfural (2.20 g, 20 mmol)and 7-carboxyheptyltriphenylphosphonium bromide (9.71 g, 20 mmol) in THF(100 mL) by a Wittig reaction. Kugelrohr distillation afforded theproduct (2.35 g, 50%) as a yellow oil (bp 140-143° C./0.05 torr). IR:3400-2500, 1720 cm⁻¹ ; ¹ H-NMR: 1.36 (m, 4H), 1.45 (m, 2H), 1.65 (m,2H), 2.28 (s, 3H), 2.37 (t, 2H), 2.41 (m, 2H), 5.45 (m, 1H), 5.95 (d,1H), 6.12 (s, 1H), 10.00 (bs, 1H). Anal. Calcd. for C₁₄ H₂₀ O₃ : C,71.16, H, 8.53%; Found: C, 70.85, H, 8.63%. Z:E=9:91.

Example 34 9-(2-(5-Methyl)furyl)nonanoic acid

This compound was synthesized from 9-(2-(5-methyl)furyl)-8-nonenoic acid(0.94 g, 4 mmol) by a hydrogenation reaction using Pd/BaSO₄ (94 mg).Crystallization (petroleum ether) afforded the product (0.87 g, 92%) aswhite crystals (mp 49-50° C.); IR: 3400-2500, 1710 cm⁻¹ ; ¹ H-NMR: 1.30(m, 8H), 1.60 (m, 4H), 2.23 (s, 3H), 2.32 (t, 2H), 2.55 (t, 2H), 5.81(s, 2H), 8.95 (bs, 1H). Anal. Calcd. for C₁₄ H₂₂ O₃ : C, 70.56, H,9.30%; Found: C, 70.39, H, 9.33%.

Example 35 11-(2-furyl)-10-undecenoic acid

This compound was synthesized from 2-furaldehyde (1.92 g, 20 mmol) and9-carboxynonyltriphenylphosphonium bromide (10.27 g, 20 mmol) in THF(100 mL) by a Wittig reaction. Crystallization (petroleum ether)afforded the product (2.95 g, 59%) as white crystals (mp 45-46° C.); IR:3450-2500 cm⁻¹ ; ¹ H-NMR: 1.33 (m, 8H), 1.46 (m, 2H), 1.65 (m, 2H), 2.34(t, 2H), 2.45 (m, 2H), 5.55 (m, 1H), 6.18 (d, 1H), 6.25 (d, 1H), 6.38(d, 1H), 7.38 (s, 1H), 9.80 (bs, 1H). Anal. Calcd. for C₁₅ H₂₂ O₃ :C,71.97, H, 8.86%; Found: C, 71.93, H, 8.87%. Z:E=43:57.

Example 36 11-(2-Furyl)undecanoic acid

This compound was synthesized from 11-(2-furyl)-10-undecenoic acid (1.25g, 5 mmol) by a hydrogenation reaction using Pd/BaSO₄ (125 mg).Crystallization (petroleum ether) afforded the product (1.13 g, 90%) aswhite crystals (mp 40-41° C.); IR: 3450-2500, 1720 cm⁻¹ ; ¹ H-NMR: 1.30(m, 12H), 1.65 (m, 4H), 2.34 (t, 2H), 2.60 (t, 2H), 5.95 (d, 1H), 6.28(d, 1H), 7.30 (s, 1H), 10.10 (bs, 1H). Anal. Calcd. for C₁₅ H₂₄ O₃ : C,71.39, H, 9.58%; Found: C, 71.21, H, 9.63%.

Example 37 12-(2-Furyl)-11-dodecenoic acid

This compound was synthesized from 10-carboxydecyltriphenylphosphoniumbromide (10.50 g, 20 mmol) and furfural (1.92 g, 20 mmol) in THF (100mL) by a Wittig reaction. Crystallization afforded the product (2.38 g,45%) as pale yellow crystals (mp 38-39° C.); IR: 3450-2500, 1715, 695cm⁻¹ ; ¹ H-NMR: 1.35 (m, 14H), 2.35 (t, 4H), 5.60 (m, 1H), 6.30 (m, 3H),7.35 (s, 1H), 9.40 (bs, 1H). Anal. Calcd. for C₁₆ H₂₄ O₃ : C, 72.69, H,9.15; Found: C, 72.44, H, 9.06%. Z:E=43:57.

Example 38 9-(2-Thienyl)-8-nonenoic acid

This compound was synthesized from 7-carboxyheptyltriphenylphosphoniumbromide (9.71 g, 20 mmol) and 2-thiophenecarboxaldehyde (2.24 g, 20mmol) in THF (100 mL) by a Wittig reaction. Crystallization afforded theproduct (2.79 g, 59%) as white crystals (mp 45-46° C.). IR: 3400-2500,1720, 710 cm⁻¹ ; ¹ H-NMR: 1.45 (m, 8H), 2.35 (m, 4H), 5.55 (m, 1H), 6.50(d, 1H), 7.00 (m, 3H), 11.00 (bs, 1H). Anal. Calcd. for C₁₃ H₁₈ SO₂ : C,65.51, H, 7.61%; Found: C, 65.58, H, 7.63%. Z:E=75:25.

Example 39 9-(2-Thienyl)-nonanoic acid

This compound was synthesized from 9-(2-thienyl)-8-nonenoic acid (1.19g, 5 mmol) by a hydrogenation reaction using Pd/C (120 mg).Crystallization afforded the product (1.05 g, 88%) as white crystals (mp32-33° C.); IR: 3400-2500, 1715, 705 cm⁻¹ ; ¹ H-NMR: 1.35 (m, 12H), 2.35(t, 2H), 2.85 (t, 2H), 6.95 (m, 3H), 10.35 (bs, 1H). Anal. Calcd. forC₁₃ H₂₀ SO₂ : C, 64.96, H, 8.39%; Found: C, 64.81, H, 8.43%.

Example 40 9-(2-(5-Methyl)thienyl)-8-nonenoic acid

This compound was synthesized from 7-carboxyheptylphenylphosphoniumbromide (7.28 g, 15 mmol) and 2-(5-methyl)thiophenecarboxaldehyde (1.92g, 15 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation(bp 155-159° C./0.05 torr) and crystallization (petroleum ether)afforded the product (2.43 g, 48%) as pale yellow crystals (mp 38-39°C.). IR: 3400-2500, 1715 cm⁻¹ ; ¹ H-NMR: 1.40 (m, 6H), 1.65 (m, 2H),2.37 (m, 4H), 2.45 (s, 3H), 5.45+5.90 (m, 1H), 6.41 (t, 1H), 6.65 (m,1H), 6.75 (d, 1H), 10.05 (bs, 1H). Anal. Calcd. for C₁₄ H₂₀ O₂ S: C,66.63, H, 7.99%; Found: C, 66.54, H, 8.02%. Z:E=72:28.

Example 41 9-(2-(5-Methyl)thienyl)nonanoic acid

This compound was synthesized from 9-(2-(5-methyl)thienyl)-8-nonenoicacid (1.01 g, 4 mmol) by a hydrogenation reaction using Pd/C (200 mg).Crystallization (petroleum ether) afforded the product (0.91 g, 89%) aswhite crystals (mp 39-40° C.). IR: 3400-2500, 1720 cm⁻¹ ; ¹ H-NMR: 1.32(m, 8H), 1.63 (m, 4H), 2.32 (t, 2H), 2.45 (s, 3H), 2.71 (t, 2H), 6.54(s, 2H), 9.50 (bs, 1H). Anal. Calcd. for C₁₄ H₂₂ O₂ S: C, 66.10, H,8.72%; Found: C, 65.97, H, 8.72%.

Example 42 11-(2-Thienyl)-10-undecenoic acid

This compound was synthesized from 2-thiophenecarboxaldehyde (2.24 g, 20mmol) and 9-carboxynonyltriphenylphosphonium bromide (10.27 g, 20 mmol)in THF (100 mL) by a Wittig reaction. Crystallization (hexanes-ethylacetate) afforded the product (2.45 g, 46%) as white crystals (mp 61-62°C.); IR: 3450-2500, 1715 cm⁻¹ ; ¹ H-NMR: 1.31 (m, 8H), 1.45 (m, 2H),1.65 (m, 2H), 2.34 (t, 2H), 2.38 (t, 2H), 5.55 (m, 1H), 6.50 (d, 1H),6.95 (m, 2H), 7.23 (d, 2H), 10.05 (bs, 1H). Anal. Calcd. for C₁₅ H₂₂ O₂S: C, 67.63, H, 8.32%; Found: C, 67.60, H, 8.34%. Z:E=19:81.

Example 43 11-(2-Thienyl)undecanoic acid

This compound was synthesized from 11-(2-thienyl)-10-undecenoic acid(800 mg, 3 mmol) by a hydrogenation reaction using Pd/C (80 mg).Crystallization (petroleum ether) afforded the product (0.73 g, 91%) aswhite crystals (mp 41-42° C.): IR: 3450-2500, 1715 cm⁻¹ ; ¹ H-NMR: 1.30(m, 12H), 1.63 (m, 4H), 2.32 (t, 2H), 2.80 (t, 2H), 6.78 (d, 1H), 6.90(t, 1H), 7.10 (d, 1H), 9.80 (bs, 1H). Anal. Calcd. for C₁₅ H₂₄ O₂ S: C,67.12, H, 9.01%; Found: C, 67.55, H, 8.89%.

Example 44

The biological activity of a panel of fatty acid analogs that had beentested previously as substrates for purified E. coli-derived S.cerevisiae myristoylCoA:protein N-myristoyltransferase (Nmt) were testedfor toxicity against trypanosomes as potential candidates foranti-trypanosomal drugs. For purposes of comparison, severaloxatetradecanoic acids described in U.S. Pat. No. 5,151,445 asinhibitors of the growth and viability of bloodstream trypanosomeparasites were included in the test panel. For convenience, this panelof fatty acid analogs was subdivided based on chemical differences intheir secondary functional group. These functional groups vary withrespect to their polarity, steric bulk, conformations, and to a limiteddegree, overall chain length. The 247 compounds thus tested areorganized in Table 2, below, into 20 families. Several of thesefunctional groups should have complex effects on both conformation andstereoelectronic properties (e.g. analogs with ester) whereas otherswill predominantly affect only one of these properties (e.g.conformation but not polarity in the case of olefins; polarity but notconformation in the case of oxatetradecanoic acids). In many of thesefamilies, the effects of the functional group have been assessed atevery possible position from C3 through C13 in tetradecanoic acid (e.g.see the thia-and oxotetradecanoic acids listed in Table 2).

To perform the large scale testing, a reproducible and rapid assay wasemployed. The method exploits the fact that growing trypanosomes secretelarge amounts of pyruvic acid, an end product of glucose catabolism(Operdoes, 1987). The pyruvic acid causes a change in color of thephenol red indicator present in the culture medium, providing aquantitative measure of cell growth. A similar assay has been publishedpreviously (Zinsstag et al., 1991). The detailed assay procedures usedherein are as follows:

Trypanosomes were grown in the presence of analogs or positive andnegative controls (11-oxatetradecanoic acid and the ethanol solvent,respectively). To avoid bias in data interpretation analog solutionswere identified only by a code number. To evaluate reliability andreproducibility of the assay, several analogs were coded twice. Allcoded analogs were tested in quadruplicate on at least two separateoccasions. After a standard growth period, the absorbance of the culturewas determined at 550 nm and 405 nm and an efficacy value calculatedfrom the ratio of these absorbances. Results from a representative testare shown in FIG. 1. This set of coded compounds included samples ofethanol and 11-oxatetradecanoic acid as both coded and uncoded samples(compounds E and 24 and O11 and 27 respectively). The excellentagreement between these samples and the controls attests to thereproducibility of this assay. Quadruplicate samples were generally eachwithin 5% of the mean, and the ratio of the absorbance at 550 nm and 405nm obtained for 11-oxatetradecanoic acid averaged 1.12 with a standarderror of 0.04 for over 100 determinations during a 6 month period.

The analogs were grouped in terms of efficacy, defining 10 μM11-oxatetradecanoic acid as the center of group 3 and the ethanolcontrols as the center of group 1 (FIG. 1). The range of values werecalculated defining each group independently for each test based on the11-oxatetradecanoic acid and ethanol values in that trial. Thiscontrolled for any differences in medium or cell growth. All compoundsclassified as group 3 were tested at least twice. After screening andcategorizing all analogs in this manner, the code was broken and thestructures of the compounds were matched with their efficacy. Note that11-oxa-, 13-oxa-, and 6-oxatetradecanoic acids fall in groups 3, 2, and1, respectively. These values correlate well with their effects ontrypanosome growth assessed by cell counts using a hemocytometer(Doering et al., 1991).

FIG. 2 shows the structures of the 20 most active compounds whichcollectively define group 3. They are presented in decreasing order ofpotency in Table 1, above, and as structural groups in FIG. 2. Nine ofthe compounds are either thiatetradecanoic or oxatetradecanoic acids.The ether functional group is also present in conjunction with anaromatic residue in three other compounds. An additional four analogscontain oxygen, either in the form of a ketocarbonyl or an ester group.The remaining structures include 13-nitrotridecanoic acid and threeunsaturated, fourteen carbon carboxylic acids. 9-Tetradecynoic acid wasthe most potent anti-trypanosomal agent identified among the 247compounds screened.

Cells Used for Growth Assays

For toxicity assays, cloned T. brucei (strain 427) of variant antigentype 221 (obtained from G. A. M. Cross, Rockefeller University) wereharvested from CD-1 mice at a parasitemia of 2-5×10⁸ trypanosomes/mL.After centrifugation of the infected blood (430×g; 8 min; 4° C.), theupper portion of the buffy coat was retained, with care taken to avoidcontamination with erythrocytes. This material, consisting predominantlyof trypanosomes, was then resuspended in BBS containing 1 mg/mL fattyacid free bovine serum albumin. The suspension was centrifuged (3,000×g;8 min; 4° C.), and the cell pellet resuspended in culture medium to afinal density of 1.5×10⁷ cells/mL. (The composition of this culturemedium was as described above except that 40 μM monothioglycerol wasadded; Duszenko et al., 1985; Doering et al., 1990; Hamm et al., 1990.)The doubling time of trypanosomes under these culture conditions isapproximately 6 h at 37° C.

Growth Assay

This rapid assay, which can accommodate multiple samples, depends onmeasurement of the color change produced in the medium's phenol redindicator dye due to acidification by growing trypanosomes. Stocks ofanalogs (10 mM in absolute ethanol, identified only by a code number)were diluted in culture medium to twice the concentration to be tested.Aliquots of 100 μL were dispensed into 96-well microtiter plates andwarmed to 37° C. in a 5% CO₂ incubator before the addition of an equalvolume of cell suspension (1.5×10⁷ /mL, see above). All assays wereperformed in quadruplicate in each plate. Control wells includedappropriately diluted ethanol (which had no effect on cell growth) and10 μM 11-oxatetradecanoic acid. The plate was incubated for 36 h at 37°C. and then stored at 4° C. for 12 h to allow equilibration of CO₂ inthe medium with that in air. The absorbance of each sample, at 550 nmand 405 nm (values chosen based on the absorption spectra of fresh andacidified media), was then read in a UV_(max) kinetic microplate reader(Molecular Devices). To control for any variation in sample volume, theratio of absorbance at 550 nm to absorbance at 405 nm for each well wascalculated. This ratio was then averaged for each quadruplicate set andnormalized to the average obtained in the set of control wellscontaining 10 μM 11-oxatetradecanoic acid, yielding an "efficacy value".

                                      TABLE 2                                     __________________________________________________________________________    Screening fatty acid analogs for toxicity against T. brucei type 221          Structure               Reference    Efficacy                                                                           Group.sup.1                         __________________________________________________________________________    Saturated Fatty Acids.sup.2                                                     CH.sub.3 --(CH.sub.2).sub.6 --COOH  1                                         CH.sub.3 --(CH.sub.2).sub.8 --COOH  1                                         CH.sub.3 --(CH.sub.2).sub.10 --COOH  1                                        CH.sub.3 --(CH.sub.2).sub.11 --COOH  1                                        CH.sub.3 --(CH.sub.2).sub.12 --COOH  1                                        CH.sub.3 --(CH.sub.2).sub.13 --COOH  1                                        CH.sub.3 --(CH.sub.2).sub.14 --COOH  1                                        CH.sub.3 --(CH.sub.2).sub.16 --COOH  1                                        CH.sub.3 --(CH.sub.2).sub.18 --COOH  1                                        Oxatetradecanoic acids                                                        CH.sub.3 --O--(CH.sub.2).sub.11 --COOH Kishore et al., 1991 2                 CH.sub.3 --CH.sub.2 --O--(CH.sub.2).sub.10 --COOH Kishore et al., 1991                                                1                                     CH.sub.3 --(CH.sub.2).sub.2 --O--(CH.sub.2).sub.9 --COOH Kishore et                                                   al., 1991 3*.sup.3                    CH.sub.3 --(CH.sub.2).sub.3 --O--(CH.sub.2).sub.8 --COOH Kishore et                                                   al., 1991 3*                          CH.sub.3 --(CH.sub.2).sub.5 --O--(CH.sub.2).sub.6 --COOH Kishore et                                                   al., 1991 3b                          CH.sub.3 --(CH.sub.2).sub.6 --O--(CH.sub.2).sub.5 --COOH Kishore et                                                   al., 1991 3**.sup.4                   CH.sub.3 --(CH.sub.2).sub.7 --O--(CH.sub.2).sub.4 --COOH Kishore et                                                   al., 1991 1                           CH.sub.3 --(CH.sub.2).sub.8 --O--(CH.sub.2).sub.3 --COOH Kishore et                                                   al., 1991 3*                          CH.sub.3 --(CH.sub.2).sub.9 --O--(CH.sub.2).sub.2 --COOH Kishore et                                                   al., 1991 2                           CH.sub.3 --(CH.sub.2).sub.10 --O--CH.sub.2 --COOH Kishore et al., 1991                                                1                                     Thiatetradecanoic acids                                                       CH.sub.3 --S--(CH.sub.2).sub.11 --COOH Kishore et al., 1991 3*                CH.sub.3 --CH.sub.2 --S--(CH.sub.2).sub.10 --COOH Kishore et al., 1991                                                2                                     CH.sub.3 --(CH.sub.2).sub.3 --S--(CH.sub.2).sub.8 --COOH Kishore et                                                   al., 1991 2                           CH.sub.3 --(CH.sub.2).sub.4 --S--(CH.sub.2).sub.7 --COOH Kishore et                                                   al., 1991 3b*                         CH.sub.3 --(CH.sub.2).sub.5 --S--(CH.sub.2).sub.6 --COOH Kishore et                                                   al., 1991 2                           CH.sub.3 --(CH.sub.2).sub.6 --S--(CH.sub.2).sub.5 --COOH Kishore et                                                   al., 1991 3**                         CH.sub.3 --(CH.sub.2).sub.7 --S--(CH.sub.2).sub.4 --COOH Kishore et                                                   al., 1991 2a                          CH.sub.3 --(CH.sub.2).sub.8 --S--(CH.sub.2).sub.3 --COOH Kishore et                                                   al., 1991 3**                         CH.sub.3 --(CH.sub.2).sub.9 --S--(CH.sub.2).sub.2 --COOH Kishore et                                                   al., 1991 1                           CH.sub.3 --(CH.sub.2).sub.10 --S--CH.sub.2 --COOH Kishore et al., 1991                                                1                                   Myristic acid analogs containing sulfur and/or oxygen substituents            CH.sub.3 --CH.sub.2 --S--(CH.sub.2).sub.5 --S--(CH.sub.2).sub.4 --COOH                                Kishore et al., 1991                                                                            1                                     CH.sub.3 --CH.sub.2 --S--(CH.sub.2).sub.2 --O--(CH.sub.2).sub.7 --COOH                                                Kishore et al., 1991 2                CH.sub.3 --CH.sub.2 --O--(CH.sub.2).sub.2 --S--(CH.sub.2).sub.7 --COOH                                                Kishore et al., 1991 1                CH.sub.3 --CH.sub.2 --O--(CH.sub.2).sub.5 --S--(CH.sub.2).sub.4 --COOH                                                Kishore et al., 1991 1                CH.sub.3 --O--(CH.sub.2).sub.2 --O--(CH.sub.2).sub.2 --O--(CH.sub.2).sub                                              .5 --COOH Kishore et al., 1991                                                1                                     Oxotetradecanoic acids                                                        CH.sub.3 --CO--(CH.sub.2).sub.11 --COOH Devadas et al., 1992 2                CH.sub.3 --CH.sub.2 --CO--(CH.sub.2).sub.10 --COOH Devadas et al., 1992                                               1                                     CH.sub.3 --(CH.sub.2).sub.2 --CO--(CH.sub.2).sub.9 --COOH Devadas et                                                  al., 1992 2a*                         CH.sub.3 --(CH.sub.2).sub.3 --CO--(CH.sub.2).sub.8 --COOH Devadas et                                                  al., 1992 2b                          CH.sub.3 --(CH.sub.2).sub.4 --CO--(CH.sub.2).sub.7 --COOH Devadas et                                                  al., 1992 2a*                         CH.sub.3 --(CH.sub.2).sub.5 --CO--(CH.sub.2).sub.6 --COOH Devadas et                                                  al., 1992 1                           CH.sub.3 --(CH.sub.2).sub.6 --CO--(CH.sub.2).sub.5 --COOH Devadas et                                                  al., 1992 3**                         CH.sub.3 --(CH.sub.2).sub.7 --CO--(CH.sub.2).sub.4 --COOH Devadas et                                                  al., 1992 1                           CH.sub.3 --(CH.sub.2).sub.8 --CO--(CH.sub.2).sub.3 --COOH Devadas et                                                  al., 1992 3b*                         CH.sub.3 --(CH.sub.2).sub.9 --CO--(CH.sub.2).sub.2 --COOH Devadas et                                                  al., 1992 2                           CH.sub.3 --(CH.sub.2).sub.10 --CO--CH.sub.2 --COOH Devadas et al., 1992                                               1                                     Myristic acid analogs containing ester groups                                 CH.sub.3 --O--CO--(CH.sub.2).sub.10 --COOH Devadas et al., 1992 2                                                      CH.sub.3 --CH.sub.2 --O--CO--(C                                              H.sub.2).sub.9 --COOH Devadas                                                 et al., 1992 1                        CH.sub.3 --(CH.sub.2).sub.2 --O--CO--(CH.sub.2).sub.8 --COOH Devadas et                                               al., 1992 2                           CH.sub.3 --(CH.sub.2).sub.3 --O--CO--(CH.sub.2).sub.7 --COOH Devadas et                                               al., 1992 2a                          CH.sub.3 --(CH.sub.2).sub.4 --O--CO--(CH.sub.2).sub.6 --COOH Devadas et                                               al., 1992 1a                          CH.sub.3 --(CH.sub.2).sub.5 --O--CO--(CH.sub.2).sub.5 --COOH Devadas et                                               al., 1992 2b                          CH.sub.3 --(CH.sub.2).sub.6 --O--CO--(CH.sub.2).sub.4 --COOH Devadas et                                               al., 1992 2                           CH.sub.3 --(CH.sub.2).sub.7 --O--CO--(CH.sub.2).sub.3 --COOH Devadas et                                               al., 1992 3                           CH.sub.3 --(CH.sub.2).sub.8 --O--CO--(CH.sub.2).sub.2 --COOH Devadas et                                               al., 1992 3b*                         CH.sub.3 --(CH.sub.2).sub.9 --O--CO--CH.sub.2 --COOH Devadas et al.,                                                  1992 1                                CH.sub.3 --CH.sub.2 --O--CO--(CH.sub.2).sub.10 --COOH Devadas et al.,                                                 1992 1                                Myristic acid analogs containing amide groups                                 CH.sub.3 --NH--CO--(CH.sub.2).sub.10 --COOH Devadas et al., 1992 1                                                     CH.sub.3 --(CH.sub.2).sub.2                                                  --NH--CO--(CH.sub.2).sub.8                                                    --COOH Devadas et al., 1992 1                                                  CH.sub.3 --(CH.sub.2).sub.3                                                  --NH--CO--(CH.sub.2).sub.7                                                    --COOH Devadas et al., 1992 1                                                  CH.sub.3 --(CH.sub.2).sub.4                                                  --NH--CO--(CH.sub.2).sub.6                                                    --COOH Devadas et al., 1992 1                                                  CH.sub.3 --(CH.sub.2).sub.5                                                  --NH--CO--(CH.sub.2).sub.5                                                    --COOH Devadas et al., 1992 1                                                  CH.sub.3 --(CH.sub.2).sub.6                                                  --NH--CO--(CH.sub.2).sub.4                                                    --COOH Devadas et al., 1992 1                                                  CH.sub.3 --(CH.sub.2).sub.7                                                  --NH--CO--(CH.sub.2).sub.3                                                    --COOH Devadas et al., 1992 1                                                  CH.sub.3 --(CH.sub.2).sub.8                                                  --NH--CO--(CH.sub.2).sub.2                                                    --COOH Devadas et al., 1992 1                                                  CH.sub.3 --(CH.sub.2).sub.9                                                  --NH--CO--CH.sub.2 --COOH                                                     Devadas et al., 1992 1                Myristic acid analogs containing acylamino amide groups                       CH.sub.3 --CO--NH--(CH.sub.2).sub.10 --COOH Devadas et al., 1992 1                                                     CH.sub.3 --(CH.sub.2).sub.3                                                  --CO--NH--(CH.sub.2).sub.7                                                    --COOH Devadas et al., 1992 1                                                  CH.sub.3 --(CH.sub.2).sub.4                                                  --CO--NH--(CH.sub.2).sub.6                                                    --COOH Devadas et al., 1992 1                                                  CH.sub.3 --(CH.sub.2).sub.5                                                  --CO--NH--(CH.sub.2).sub.5                                                    --COOH Devadas et al., 1992 1                                                  CH.sub.3 --(CH.sub.2).sub.6                                                  --CO--NH--(CH.sub.2).sub.4                                                    --COOH Devadas et al., 1992 1                                                  CH.sub.3 --(CH.sub.2).sub.7                                                  --CO--NH--(CH.sub.2).sub.3                                                    --COOH Devadas et al., 1992 1                                                  CH.sub.3 --(CH.sub.2).sub.8                                                  --CO--NH--(CH.sub.2).sub.2                                                    --COOH Devadas et al., 1992 1                                                  CH.sub.3 --(CH.sub.2).sub.9                                                  --CO--NH--CH.sub.2 --COOH                                                     Devadas et al., 1992 1a                                                        Nitroalkylcarboxylic acids                                                    O.sub.2 N--(CH.sub.2).sub.9                                                  --COOH Lu et al., 1994.sup.5 1                                                 O.sub.2 N--(CH.sub.2).sub.10                                                 --COOH Lu et al., 1994 2a                                                      O.sub.2 N--(CH.sub.2).sub.12                                                 --COOH Lu et al., 1994 3                                                       Halogenated analogs                  Br--(CH.sub.2).sub.12 --COOH Lu et al., 1994 2                                Br--(CH.sub.2).sub.13 --COOH Lu et al., 1994 2                                F.sub.3 C--(CH.sub.2).sub.12 --COOH Lu et al., 1994 1                         F.sub.3 C--CH═CH--(CH.sub.2).sub.10 --COOH Lu et al., 1994 1                                                       Tetradecenoic acids                CH.sub.2 ═CH--(CH.sub.2).sub.11 --COOH                                                            Kishore et al., 1991                                                                            1                                     CH.sub.3 --CH═CH--(CH.sub.2).sub.10 --COOH Kishore et al., 1991                                                   Z12.sup.6 1                           CH.sub.3 --CH.sub.2 --CH═CH--(CH.sub.2).sub.9 --COOH Kishore et                                                   al., 1991 Z11 2b                      CH.sub.3 --(CH.sub.2).sub.2 --CH═CH--(CH.sub.2).sub.8 --COOH                                                      Kishore et al., 1991 Z10 1                                                     CH.sub.3 --(CH.sub.2).sub.4                                                  --CH═CH--(CH.sub.2).sub.6                                                 --COOH Kishore et al., 1991 Z8                                                1a                                    CH.sub.3 --(CH.sub.2).sub.5 --CH═CH--(CH.sub.2).sub.5 --COOH                                                      Kishore et al., 1991 Z7 2b                                                     CH.sub.3 --(CH.sub.2).sub.5                                                  --CH═CH--(CH.sub.2).sub.5                                                 --COOH Kishore et al., 1991                                                   E7.sup.7 1                            CH.sub.3 --(CH.sub.2).sub.6 --CH═CH--(CH.sub.2).sub.4 --COOH                                                      Kishore et al., 1991 E6 2b                                                     CH.sub.3 --(CH.sub.2).sub.6                                                  --CH═CH--(CH.sub.2).sub.4                                                 --COOH Kishore et al., 1991 Z6                                                1                                     Isomer mixture: 15% E6, 85% Z6 Kishore et al., 1991 E:Z6 1                    CH.sub.3 --(CH.sub.2).sub.7 --CH═CH--(CH.sub.2).sub.3 --COOH                                                      Kishore et al., 1991 E5 1                                                      CH.sub.3 --(CH.sub.2).sub.7                                                  --CH═CH--(CH.sub.2).sub.3                                                 --COOH Kishore et al., 1991 Z5                                                1                                     CH.sub.3 --(CH.sub.2).sub.8 --CH═CH--(CH.sub.2).sub.2 --COOH                                                      Kishore et al., 1991 Z4 1                                                      CH.sub.3 --(CH.sub.2).sub.8                                                  --CH═CH--(CH.sub.2).sub.2                                                 --COOH Kishore et al., 1991 E4                                                1                                     CH.sub.3 --(CH.sub.2).sub.9 --CH═CH--CH.sub.2 --COOH Kishore et                                                   al., 1991 Z3 1                        CH.sub.3 --(CH.sub.2).sub.10 --CH═CH--COOH Kishore et al., 1991 E2                                                1                                     CH.sub.3 --(CH.sub.2).sub.10 --CH═CH--COOH Kishore et al., 1991 Z2                                                1                                     CH.sub.3 --CH.sub.2 --CH═CH--(CH.sub.2).sub.3 --COOH Rudnick et                                                   al., 1992 C8:Z5 1                     CH.sub.3 --(CH.sub.2).sub.3 --CH═CH--(CH.sub.2).sub.3 --COOH                                                      Rudnick et al., 1992 C10:Z5 1                                                  CH.sub.3 --(CH.sub.2).sub.5                                                  --CH═CH--(CH.sub.2).sub.3                                                 --COOH Rudnick et al., 1992                                                   C12:Z5 1                              CH.sub.3 --(CH.sub.2).sub.10 --CH═CH--(CH.sub.2).sub.2 --COOH                                                     Rudnick et al., 1992 C16:Z4 1                                                  CH.sub.3 --(CH.sub.2).sub.9                                                  --CH═CH--(CH.sub.2).sub.3                                                 --COOH Rudnick et al., 1992                                                   C16:Z5 1                              CH.sub.3 --(CH.sub.2).sub.8 --CH═CH--(CH.sub.2).sub.4 --COOH                                                      Rudnick et al., 1992 C16:Z6 1                                                  CH.sub.3 --(CH.sub.2).sub.10                                                 --CH═CH--(CH.sub.2).sub.3                                                 --COOH Rudnick et al., 1992                                                   C17:Z5 1                              CH.sub.3 --(CH.sub.2).sub.11 --CH═CH--(CH.sub.2).sub.3 --COOH                                                     Rudnick et al., 1992 C18:Z5 1                                                  Tetradecadienoic acids                                                        CH.sub.3 --(CH.sub.2).sub.2                                                  --CH═CH--CH═CH--(CH.sub.                                              2).sub.6 --COOH See Examples  1       CH.sub.3 --(CH.sub.2).sub.4 --CH═CH--CH═CH--(CH.sub.2).sub.4                                                  --COOH See Examples  2b                                                        CH.sub.3 --(CH.sub.2).sub.5                                                  --CH═CH--CH═CH--(CH.sub.                                              2).sub.3 --COOH See Examples  3       Tetradecynoic acids                                                           HC.tbd.C--(CH.sub.2).sub.11 --COOH Kishore et al., 1991  2b                   CH.sub.3 --C.tbd.C--(CH.sub.2).sub.10 --COOH Kishore et al., 1991  1                                                   CH.sub.3 CH.sub.2 --C.tbd.C--(C                                              H.sub.2).sub.9 --COOH Kishore                                                 et al., 1991  1                       CH.sub.3 --(CH.sub.2).sub.2 --C.tbd.C--(CH.sub.2).sub.8 --COOH Kishore                                                et al., 1991  2                       CH.sub.3 --(CH.sub.2).sub.3 --C.tbd.C--(CH.sub.2).sub.7 --COOH Kishore                                                et al., 1991  3a                      CH.sub.3 --(CH.sub.2).sub.4 --C.tbd.C--(CH.sub.2).sub.6 --COOH Kishore                                                et al., 1991  3                       CH.sub.3 --(CH.sub.2).sub.5 --C.tbd.C--(CH.sub.2).sub.5 --COOH Kishore                                                et al., 1991  2                       CH.sub.3 --(CH.sub.2).sub.6 --C.tbd.C--(CH.sub.2).sub.4 --COOH Kishore                                                et al., 1991  2                       CH.sub.3 --(CH.sub.2).sub.7 --C.tbd.C--(CH.sub.2).sub.3 --COOH Kishore                                                et al., 1991  2                       CH.sub.3 --(CH.sub.2).sub.8 --C.tbd.C--(CH.sub.2).sub.2 --COOH Kishore                                                et al., 1991  1                       CH.sub.3 --(CH.sub.2).sub.9 --C.tbd.C--CH.sub.2 --COOH Kishore et al.,                                                1991  1                               CH.sub.3 --(CH.sub.2).sub.10 --C.tbd.C--COOH Kishore et al., 1991  1                                                   CH.sub.3 --(CH.sub.2).sub.7                                                  --C.tbd.C--(CH.sub.2).sub.2                                                   --COOH Rudnick et al., 1992                                                   C13:Y4.sup.8 1                        CH.sub.3 --(CH.sub.2).sub.6 --C.tbd.C--(CH.sub.2).sub.3 --COOH Rudnick                                                et al., 1992 C13:Y5 1                 CH.sub.3 --(CH.sub.2).sub.5 --C.tbd.C--(CH.sub.2).sub.4 --COOH Rudnick                                                et al., 1992 C13:Y6 2b                CH.sub.3 --(CH.sub.2).sub.9 --C.tbd.C--(CH.sub.2).sub.2 --COOH Rudnick                                                et al., 1992 C15:Y4 1                 CH.sub.3 --(CH.sub.2).sub.8 --C.tbd.C--(CH.sub.2).sub.3 --COOH Rudnick                                                et al., 1992 C15:Y5 1                 CH.sub.3 --(CH.sub.2).sub.7 --C.tbd.C--(CH.sub.2).sub.4 --COOH Rudnick                                                et al., 1992 C15:Y6 1                 CH.sub.3 --(CH.sub.2).sub.10 --C.tbd.C--(CH.sub.2).sub.2 --COOH Rudnick                                               et al., 1992 C16:Y4 1                 CH.sub.3 --(CH.sub.2).sub.9 --C.tbd.C--(CH.sub.2).sub.3 --COOH Rudnick                                                et al., 1992 C16:Y5 1                 CH.sub.3 --(CH.sub.2).sub.8 --C.tbd.C--(CH.sub.2).sub.4 --COOH Rudnick                                                et al., 1992 C16:Y6 1                 Aromatic analogs                                                              11 Carbon Equivalent Length.sup.9                                             C.sub.6 H.sub.5 --(CH.sub.2).sub.7 --COOH Kishore et al., 1991  2b                                                     C.sub.6 H.sub.5 --(CH.sub.2).su                                              b.2 --CH═CH--(CH.sub.2).sub.                                              3 --COOH Kishore et al., 1991                                                 1                                     12 Carbon Equivalent Length                                                   C.sub.6 H.sub.5 --(CH.sub.2).sub.8 --COOH Kishore et al., 1991  1                                                      C.sub.6 H.sub.5 --CH═CH--(C                                              H.sub.2).sub.6 --COOH Kishore                                                 et al., 1991  1a                      C.sub.6 H.sub.5 --(CH.sub.2).sub.2 --CH═CH--(CH.sub.2).sub.4 --COOH                                               Kishore et al., 1991  1                                                        C.sub.6 H.sub.5 --O--(CH.sub.2)                                              .sub.7 --COOH See Examples  1                                                  13 Carbon Equivalent Length                                                   C.sub.6 H.sub.5 --(CH.sub.2).su                                              b.9 --COOH Kishore et al., 1991                                                2b                                   CH.sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Kishore et al.,                                                  1991  1                               CH.sub.3 --CH.sub.2 --C.sub.6 H.sub.4 --(CH.sub.2).sub.7 --COOH Kishore                                               et al., 1991  2b                      CH.sub.3 --(CH.sub.2).sub.2 --C.sub.6 H.sub.4 --(CH.sub.2).sub.6 --COOH                                               Kishore et al., 1991  1                                                        CH.sub.3 --(CH.sub.2).sub.3                                                  --C.sub.6 H.sub.4 --(CH.sub.2).s                                              ub.5 --COOH Kishore et al.,                                                   1991  1                               CH.sub.3 --(CH.sub.2).sub.4 --C.sub.6 H.sub.4 --(CH.sub.2).sub.4 --COOH                                               Gokel et al., 1992  1                 CH.sub.3 --(CH.sub.2).sub.5 --C.sub.6 H.sub.4 --(CH.sub.2).sub.3 --COOH                                               Gokel et al., 1992  1a                CH.sub.3 --(CH.sub.2).sub.6 --C.sub.6 H.sub.4 --(CH.sub.2).sub.2 --COOH                                               Gokel et al., 1992  1                 C.sub.6 H.sub.5 --CH.sub.2 --CH═CH--(CH.sub.2).sub.6 --COOH Kishore                                               et al., 1991  1                       CH.sub.3 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Kishore                                               et al., 1991  1                       CH.sub.3 --CH.sub.2 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.5                                                   --COOH Kishore et al., 1991  1                                                 CH.sub.3 --(CH.sub.2).sub.2                                                  --C.sub.6 H.sub.4 --CH═CH--(                                              CH.sub.2).sub.4 --COOH Kishore                                                et al., 1991  1                       CH.sub.3 --(CH.sub.2).sub.3 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).su                                              b.3 --COOH Kishore et al., 1991                                                1                                    CH.sub.3 --(CH.sub.2).sub.4 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).su                                              b.2 --COOH Gokel et al., 1992                                                 1                                     CH.sub.3 --(CH.sub.2).sub.5 --C.sub.6 H.sub.4 --CH═CH--CH.sub.2                                                   --COOH Gokel et al., 1992  1                                                   CH.sub.3 --(CH.sub.2).sub.6                                                  --C.sub.6 H.sub.4 --CH═CH--C                                              OOH Gokel et al., 1992  1                                                      CH.sub.3 --O--C.sub.6 H.sub.4                                                --(CH.sub.2).sub.7 --COOH See                                                 Examples  1                           CH.sub.3 --CH.sub.2 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.6 --COOH See                                                Examples  1                           CH.sub.3 --(CH.sub.2).sub.2 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.5                                                   --COOH See Examples  1                CH.sub.3 --(CH.sub.2).sub.3 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.4                                                   --COOH Gokel et al., 1992  3                                                   CH.sub.3 --(CH.sub.2).sub.4                                                  --O--C.sub.6 H.sub.4 --(CH.sub.2                                              ).sub.3 --COOH Gokel et al.,                                                  1992  1                               CH.sub.3 --(CH.sub.2).sub.5 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.2                                                   --COOH Gokel et al., 1992  1                                                   CH.sub.3 --O--C.sub.6 H.sub.4                                                --CH═CH--(CH.sub.2).sub.5                                                 --COOH See Examples  1                CH.sub.3 --CH.sub.2 --O--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.4                                                --COOH See Examples  1                CH.sub.3 --(CH.sub.2).sub.2 --O--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2)                                              .sub.3 --COOH See Examples  1                                                  CH.sub.3 --(CH.sub.2).sub.3                                                  --O--C.sub.6 H.sub.4 --CH═CH                                              --(CH.sub.2).sub.2 --COOH Gokel                                               et al., 1992  1                       CH.sub.3 --(CH.sub.2).sub.4 --O--C.sub.6 H.sub.4 --CH═CH--CH.sub.2                                                --COOH Gokel et al., 1992  1                                                   CH.sub.3 --(CH.sub.2).sub.5                                                  --O--C.sub.6 H.sub.4 --CH═CH                                              --COOH Gokel et al., 1992  1                                                   C.sub.6 H.sub.5 --O--(CH.sub.2)                                              .sub.8 --COOH See Examples  1                                                  C.sub.6 H.sub.5 --S--(CH.sub.2)                                              .sub.8 --COOH See Examples  1                                                  C.sub.6 H.sub.5 --CH.sub.2                                                   --O--(CH.sub.2).sub.7 --COOH                                                  See Examples  1                       C.sub.6 H.sub.5 --CH.sub.2 --S--(CH.sub.2).sub.7 --COOH See Examples  1       14 Carbon Equivalent Length                                                   C.sub.6 H.sub.5 --(CH.sub.2).sub.10 --COOH Heuckeroth et al., 1990  2b                                                 CH.sub.3 --C.sub.6 H.sub.4                                                   --(CH.sub.2).sub.9 --COOH                                                     Kishore et al., 1991  1                                                        CH.sub.3 --CH.sub.2 --C.sub.6                                                H.sub.4 --(CH.sub.2).sub.8                                                    --COOH Kishore et al., 1991  1a       CH.sub.3 --(CH.sub.2).sub.2 --C.sub.6 H.sub.4 --(CH.sub.2).sub.7 --COOH                                               See Examples  1                       CH.sub.3 --(CH.sub.2).sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.6 --COOH                                               See Examples  1                       CH.sub.3 --(CH.sub.2).sub.4 --C.sub.6 H.sub.4 --(CH.sub.2).sub.5 --COOH                                               See Examples  1                       CH.sub.3 --(CH.sub.2).sub.5 --C.sub.6 H.sub.4 --(CH.sub.2).sub.4 --COOH                                               Gokel et al., 1992  1                 CH.sub.3 --(CH.sub.2).sub.6 --C.sub.6 H.sub.4 --(CH.sub.2).sub.3 --COOH                                               Gokel et al., 1992  1                 C.sub.6 H.sub.5 --(CH.sub.2).sub.2 --CH═CH--(CH.sub.2).sub.6 --COOH                                               Heuckeroth et al., 1990  1                                                     CH.sub.3 --C.sub.6 H.sub.4                                                   --CH═CH--(CH.sub.2).sub.7                                                 --COOH Kishore et al., 1991  1                                                 CH.sub.3 --CH.sub.2 --C.sub.6                                                H.sub.4 --CH═CH--(CH.sub.2).                                              sub.6 --COOH Kishore et al.,                                                  1991  1                               CH.sub.3 --(CH.sub.2).sub.2 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).su                                              b.5 --COOH See Examples  1                                                     CH.sub.3 --(CH.sub.2).sub.3                                                  --C.sub.6 H.sub.4 --CH═CH--(                                              CH.sub.2).sub.4 --COOH See                                                    Examples  1                           CH.sub.3 --(CH.sub.2).sub.4 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).su                                              b.3 --COOH See Examples  1                                                     CH.sub.3 --(CH.sub.2).sub.5                                                  --C.sub.6 H.sub.4 --CH═CH--(                                              CH.sub.2).sub.2 --COOH Gokel et                                               al., 1992  1                          CH.sub.3 --(CH.sub.2).sub.6 --C.sub.6 H.sub.4 --CH═CH--CH.sub.2                                                   --COOH Gokel et al., 1992  1                                                   CH.sub.3 --O--C.sub.6 H.sub.4                                                --(CH.sub.2).sub.8 --COOH                                                     Kishore et al., 1991  1a                                                       CH.sub.3 --CH.sub.2 --O--C.sub.                                              6 H.sub.4 --(CH.sub.2).sub.7                                                  --COOH Kishore et al., 1991  1a       CH.sub.3 --(CH.sub.2).sub.2 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.6                                                   --COOH See Examples  1                CH.sub.3 --(CH.sub.2).sub.3 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.5                                                   --COOH See Examples  1                CH.sub.3 --(CH.sub.2).sub.4 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.4                                                   --COOH Gokel et al., 1992  3                                                   CH.sub.3 --(CH.sub.2).sub.5                                                  --O--C.sub.6 H.sub.4 --(CH.sub.2                                              ).sub.3 --COOH Gokel et al.,                                                  1992  1                               CH.sub.3 --(CH.sub.2).sub.6 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.2                                                   --COOH Gokel et al., 1992  1                                                   CH.sub.3 --O--C.sub.6 H.sub.4                                                --CH═CH--(CH.sub.2).sub.6                                                 --COOH Kishore et al., 1991  1                                                 CH.sub.3 --CH.sub.2 --O--C.sub.                                              6 H.sub.4 --CH═CH--(CH.sub.2                                              ).sub.5 --COOH Kishore et al.,                                                1991  1a                              CH.sub.3 --(CH.sub.2).sub.2 --O--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2)                                              .sub.4 --COOH See Examples  1                                                  CH.sub.3 --(CH.sub.2).sub.3                                                  --O--C.sub.6 H.sub.4 --CH═CH                                              --(CH.sub.2).sub.3 --COOH See                                                 Examples  2a                          CH.sub.3 --(CH.sub.2).sub.4 --O--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2)                                              .sub.2 --COOH Gokel et al.,                                                   1992  2                               CH.sub.3 --(CH.sub.2).sub.5 --O--C.sub.6 H.sub.4 --CH═CH--CH.sub.2                                                --COOH Gokel et al., 1992  1                                                   CH.sub.3 --(CH.sub.2).sub.6                                                  --O--C.sub.6 H.sub.4 --CH═CH                                              --COOH Gokel et al., 1992  1                                                   C.sub.6 H.sub.5 --O--(CH.sub.2)                                              .sub.9 --COOH Kishore et al.,                                                 1991  1                               C.sub.6 H.sub.5 --S--(CH.sub.2).sub.9 --COOH Kishore et al., 1991  1                                                   CH.sub.3 --C.sub.6 H.sub.4                                                   --O--(CH.sub.2).sub.8 --COOH                                                  Kishore et al., 1991  1                                                        CH.sub.3 --C.sub.6 H.sub.4                                                   --S--(CH.sub.2).sub.8 --COOH                                                  Kishore et al., 1991  1                                                        CH.sub.3 --S--C.sub.6 H.sub.4                                                --(CH.sub.2).sub.8 --COOH                                                     Kishore et al., 1991  1                                                        CH.sub.3 --S--C.sub.6 H.sub.4                                                --CH═CH--(CH.sub.2).sub.6                                                 --COOH Kishore et al., 1991  1                                                 CH.sub.3 --CH.sub.2 --C.sub.6                                                H.sub.4 --O--(CH.sub.2).sub.7                                                 --COOH See Examples  1                15 Carbon Equivalent Length                                                   C.sub.6 H.sub.5 --(CH.sub.2).sub.11 --COOH Rapoport and Newman, 1947  1       C.sub.6 H.sub.5 --CH═CH--(CH.sub.2).sub.9 --COOH See Examples  1                                                   C.sub.6 H.sub.5 --O--(CH.sub.2)                                              .sub.10 --COOH See Examples  1                                                 Azido-aromatic analogs                                                        p-N.sub.3 --C.sub.6 H.sub.4                                                  --(CH.sub.2).sub.6 --COOH Lu et                                               al., 1994.sup.5  1                    p-N.sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.7 --COOH Lu et al., 1994                                                 1b                                    p-N.sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Lu et al., 1994                                                 1                                     m-N.sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Lu et al., 1994                                                 1                                     m-N.sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.10 --COOH Lu et al., 1994                                                1b                                    p-N.sub.3 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.5 --COOH Lu et al.,                                                   1994  1b                              m-N.sub.3 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.5 --COOH Lu et al.,                                                   1994  1                               p-N.sub.3 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.6 --COOH Lu et al.,                                                   1994  1b                              m-N.sub.3 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.6 --COOH Lu et al.,                                                   1994  1                               p-N.sub.3 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.7 --COOH Lu et al.,                                                   1994  1                               m-N.sub.3 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.7 --COOH Lu et al.,                                                   1994  1                               Nitro-aromatic analogs                                                        O.sub.2 N--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Lu et                                                 al., 1994  1                          O.sub.2 N--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.5 --COOH Lu et                                                 al., 1994  1a                         O.sub.2 N--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.4 --COOH Lu et                                                 al., 1994  1                          H.sub.2 N--C.sub.6 H.sub.4 --(CH.sub.2).sub.6 --COOH Lu et al., 1994  1       H.sub.2 N--C.sub.6 H.sub.4 --(CH.sub.2).sub.7 --COOH Lu et al., 1994  1       Halo-aromatic analogs                                                         o-F--C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Lu et al., 1994  1                                                      m-F--C.sub.6 H.sub.4 --(CH.sub.                                              2).sub.8 --COOH Lu et al., 1994                                                1                                    p-F--C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Lu et al., 1994  1a                                                     p-Cl--C.sub.6 H.sub.4 --(CH.sub                                              .2).sub.8 --COOH Lu et al.,                                                   1994  1                               p-Br--C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Lu et al., 1994  1a                                                    p-CF.sub.3 --C.sub.6 H.sub.4                                                 --(CH.sub.2).sub.8 --COOH Lu et                                               al., 1994  1                          o-F--C.sub.6 H.sub.4 --CH═C--(CH.sub.2).sub.6 --COOH Lu et al.,                                                   1994  1                               m-F--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Lu et al.,                                                  1994  1                               p-F--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Lu et al.,                                                  1994  1a                              p-Cl--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Lu et al.,                                                 1994  1                               p-Br--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Lu et al.,                                                 1994  1                               p-CF.sub.3 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Lu et                                               al., 1994  1                          Hetero-aromatic analogs                                                       CH.sub.3 --(CH.sub.2).sub.7 -furyl-(CH.sub.2).sub.2 --COOH Rudnick et                                                 al., 1992  1                          CH.sub.3 --(CH.sub.2).sub.6 -furyl-(CH.sub.2).sub.3 --COOH Rudnick et                                                 al., 1992  2                          CH.sub.3 --(CH.sub.2).sub.5 -furyl-(CH.sub.2).sub.4 --COOH Rudnick et                                                 al., 1992  3                          CH.sub.3 --(CH.sub.2).sub.4 -furyl-(CH.sub.2).sub.5 --COOH Rudnick et                                                 al., 1992  2b                         2-Furyl-(CH.sub.2).sub.8 --COOH See Examples  1                               [2-(5-CH.sub.3 -furyl)]--(CH.sub.2).sub.8 --COOH See Examples  1                                                       2-Furyl-(CH.sub.2).sub.10                                                    --COOH See Examples  2b                                                        2-Furyl-CH═CH--(CH.sub.2).s                                              ub.6 --COOH See Examples  1                                                    [2-(5-CH.sub.3 -furyl)]--CH.dbd                                              .CH--(CH.sub.2).sub.6 --COOH                                                  See Examples  1                       2-Furyl-CH═CH--(CH.sub.2).sub.8 --COOH See Examples  1                    2-Furyl-CH═CH--(CH.sub.2).sub.9 --COOH See Examples  1                    2-Thienyl-(CH.sub.2).sub.8 --COOH See Examples  1a                            2-Thienyl-(CH.sub.2).sub.9 --COOH Kishore et al., 1991  1                     [2-(5-CH.sub.3 -thienyl)]--(CH.sub.2).sub.8 --COOH See Examples  1                                                     2-Thienyl-(CH.sub.2).sub.10                                                  --COOH See Examples  2b                                                        2-Thienyl-CH═CH--(CH.sub.2)                                              .sub.6 --COOH See Examples  1                                                  [2-(5-CH.sub.3 -thienyl)]--CH.d                                              bd.CH--(CH.sub.2).sub.6 --COOH                                                See Examples  1                       2-Thienyl-CH═CH--(CH.sub.2).sub.8 --COOH See Examples  1                __________________________________________________________________________     .sup.1 Efficacy groups were assigned as described in Methods and the text     Subgroup "a" indicates compounds near the upper boundary of an efficacy       group; subgroup "b" indicates compounds at the lower boundary. The 20 mos     toxic compounds (Group 3) are highlighted in bold type.                       .sup.2 Purchased from Nu Chek Prep, Inc. (Elysian, MN)                        .sup.3 *Indicates compounds that were categorized as group 2 when tested      at 2 μM.                                                                   .sup.4 **Indicates compounds that remained in group 3 when tested at 2        μM.                                                                        .sup.5 T. Lu, Q. Li, A. Katoh, J. Hernandez, K. Duffin, E.                    JacksonMachelski, L. J. Knoll, G. W. Gokel, and J. I. Gordon, J. Biol.        Chem., 269, 5346-5357 (1994).                                                 .sup.6 Z, designates cis double bound geometry                                .sup.7 E, designates trans double bound geometry                              .sup.8 Y, indicates triple bond                                               .sup.9 Examination of CPK space filling atomic models indicates that the      width of an aromatic ring is equivalent to three methylenes.             

The antiparasitic agents described herein can be used for administrationto mammalian hosts infected with trypanosomes and the like byconventional means, preferably in formulations with pharmaceuticallyacceptable diluents and carriers. The amount of the active agent to beadministered must be an effective amount, that is, an amount which ismedically beneficial but does not present toxic effects which overweighthe advantages which accompany its use. It would be expected that theadult human dosage would normally range upward from about one milligramof the active compound. A suitable route of administration is orally inthe form of capsules, tablets, syrups, elixirs and the like, althoughparenteral administration also can be used. Appropriate formulations ofthe active compound in pharmaceutically acceptable diluents and carriersin therapeutic dosage form can be prepared by reference to general textsin the field such as, for example, Remington's Pharmaceutical Sciences,Ed. Arthur Osol, 16th ed., 1980, Mack Publishing Co., Easton, Pa.

Various other examples will be apparent to the person skilled in the artafter reading the present disclosure without departing from the spiritand scope of the invention. All such other examples are intended to beincluded within the scope of the appended claims.

References

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Bryant, M. L., Ratner, L., Duronio, R. J., Kishore, N. S., Adams, S. P.,and Gordon, J. I. (1991) Proc. Natl. Acad. Sci. USA 88, 2055-2059.

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What is claimed is:
 1. A compound having the formulaCH₃ --(CH₂)_(x)--O--C₆ H₄ --CH═CH--(CH₂)_(y) --COOH, whereinx=0-3, y=3-5, and x+y=5-6,provided that when x is 3, y is 3, and that when x is 1, y is
 4. 2. CH₃--(CH₂)₂ --O--C₆ H₄ --CH═CH--(CH₂)₄ --COOH.
 3. CH₃ --(CH₂)₃ --O--C₆ H₄--CH═CH--(CH₂)₃ --COOH.